Pathogenesis Of Attention Deficit Hyperactivity Disorder Research Articles

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.

Potential role of pre- and postnatal testosterone levels in attention-deficit/hyperactivity disorder: is there a sex difference?

ObjectiveBoth prenatal testosterone (T) exposure and postnatal T levels have been associated with developing neural circuitry and behavioral systems. This study examined the potential correlation between pre- and postnatal T levels and behavioral and neurocognitive profiles of children with attention-deficit/hyperactivity disorder (ADHD).MethodsTwo hundred ADHD patients with a mean age of 8.7±2.0 years (158 boys and 42 girls) were recruited. The ratio of the length of the right index finger (2D) to that of the right ring finger (4D) (2D/4D ratio) served as a surrogate of prenatal T exposure, and postnatal T was determined using salivary T concentration. Behavioral symptoms were evaluated using the Swanson, Nolan, and Pelham – Version IV Scale for ADHD (SNAP-IV). Neurocognitive function was assessed using the Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV) and Conners’ Continuous Performance Test (CPT).ResultsLower 2D/4D ratios were associated with comorbid disruptive behavior disorders (t=2.15, P=0.033) in all participants. Among the boys with ADHD, neither 2D/4D ratios nor salivary T levels were associated with behavioral symptoms or neurocognitive function. Among the girls with ADHD, the salivary T level was positively correlated with the Perceptual Reasoning Index of the WISC-IV (r=0.48, P=0.001) and the Confidence Index (r=0.37, P=0.017) and Omission Errors of the CPT (r=0.62, P<0.001).ConclusionFindings suggest that a higher prenatal T exposure is associated with a greater risk of developing disruptive behavior disorders, and T may exert differential neurocognitive effects between boys and girls with ADHD. However, the neurobiological mechanisms of T involved in the pathogenesis of ADHD warrant further investigation.

Glucocorticoids/glucocorticoid receptors effect on dopaminergic neurotransmitters in ADHD rats

Dexamethaone (DEX, glucocorticoid receptor agonist) and RU486 (glucocorticoid receptor inhibitor) may affect the behavior of attention deficit hyperactivity disorder (ADHD) rats, by changing the level of dopamine and noradrenaline and dopamine transporter in different regions of their brain. In this study, we have investigated the effect and the underlying mechanism of Glucocorticoids/Glucocorticoid receptors on dopaminergic neurotransmitters in ADHD Rats. Thirty male Wistar Kyoto rats (WKY) and 30 male spontaneously hypertensive rats (SHR) were respectively divided into 3 groups randomly as follows: a GR agonist group (DEX), a GR inhibitor group (RU486) and a control group (CON). Open field test and Y maze were performed respectively to assess the behavior of the rats. The levels of dopamine, norepinephrine, and dopamine transporter (DAT) in the prefrontal cortex and striatum were also tested. Our results showed that, the behavior of rats were improved after DEX treatment. We also found that the level of DA and NE increased in DEX group, but decreased significantly in RU486 group. Immunohistochemical assay showed that DAT expression level in DEX group was significantly less than that in RU486 and CON group. In conclusion, by regulation of glucocorticoid receptor, GR agonist can decrease DAT expression, resulting in the increase of DA and NE levels in brain that ameliorate hyperactivity and attention deficit in ADHD rats. Our results suggest that the effects of glucocorticoid receptor on dopaminergic neurotransmitter in the central nervous system may be involved in the pathogenesis of ADHD.

Polymorphisms of STS gene and SULT2A1 gene and neurosteroid levels in Han Chinese boys with attention-deficit/hyperactivity disorder: an exploratory investigation

This study examined the relationships among polymorphisms of the STS gene and SULT2A1 gene, dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S), and characteristics of attention-deficit/hyperactivity disorder (ADHD). We used cheek swabs to obtain the genomic DNA of 200 ADHD male probands (mean age: 8.7 years), 192 patients’ mothers and 157 patients’ fathers. Three SNPs in the STS gene (rs6639786, rs2270112, and rs17268988) and one SNP in the SULT2A1 gene (rs182420) were genotyped. Saliva samples were collected from the ADHD patients to analyze DHEA and DHEA-S levels. The behavioral symptoms were evaluated with the Swanson, Nolan, and Pelham, and Version IV Scale for ADHD (SNAP-IV), and the neuropsychological function was assessed using the Conners’ Continuous Performance Tests (CPT). We found the C allele of rs2270112 within the STS gene to be over-transmitted in males with ADHD. Polymorphisms of rs182420 within the SULT2A1 gene were not associated with ADHD. In addition, the C allele carriers of rs2270112 demonstrated significantly higher DHEA-S levels than the G allele carriers. Levels of DHEA were positively correlated with attention as measured by the CPT. These findings support a potential role in the underlying biological pathogenesis of ADHD with regard to STS polymorphisms and neurosteroid levels.

Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc.

Association of methylation status of CpG islands in DAT1 and DRD4 genes with attention deficit hyperactivity disorder

Objective To explore the difference of methylation status of CpG island in promoter region of DAT1 and DRD4 genes between children with attention deficit hyperactivity disorder (ADHD) and normal controls, and further understand the pathogenesis of ADHD from a epigenetics point of view. Methods 111 ADHD patients and 118 normal controls were enrolled in the present study. The demographic data and peripheral venous blood were collected from both groups. Bisulfite genomic sequencing (BGS) was used to confirm the methylation status of every CpG site in promoter region of DAT1 and DRD4 genes. Results No significant differences were found between ADHD patients and normal controls on percentage of methylated CpG sites in total CpG islands for both DAT1 and DRD4 (P>0.05). However, the percentage of methylation in No. 17 CpG site for DAT1 and No. 8 CpG site for DRD4 was higher in ADHD patients (23.42% and 64.86% respectively)compared with that in normal controls(11.86% and 47.46% respectively)(P<0.05). In all samples, the percentage of methylated CpG site in total CpG island for DAT1 was higher in males compared with that in females(P<0.05), whereas that for DRD4 was higher in females compared with that in males (P<0.05); the same gender difference on methylation level for DAT1 was also found in ADHD patients and for DRD4 in normal controls(P<0.05). In all samples and in ADHD patients, percentage of methylated CpG site in total CpG island for DAT1 was higher in individuals over 7 years old compared with that in individuals younger than or equal to 7 years old(P<0.05). Conclusions Methylation status of CpG island in DAT1 and DRD4 genes promoter region might correlate with ADHD susceptibility.Methylation status of CpG island in DAT1 and DRD4 genes show differences in different age span and sex. Key words: Attention deficit hyperactivity disorder; Epigenetics; DNA methylation; Dopamine transporter gene (DAT1/SLC6A3); Dopamine receptor D4 gene (DRD4)

Diminished modulation of preparatory sensorimotor mu rhythm predicts attention-deficit/hyperactivity disorder severity.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by problems in regulating attention and in suppressing disruptive motor activity, i.e. hyperactivity and impulsivity. We recently found evidence that aberrant distribution of posterior α band oscillations (8-12 Hz) is associated with attentional problems in ADHD. The sensorimotor cortex also produces strong 8-12 Hz band oscillations, namely the μ rhythm, and is thought to have a similar inhibitory function. Here, we now investigate whether problems in distributing α band oscillations in ADHD generalize to the μ rhythm in the sensorimotor domain. In a group of adult ADHD (n = 17) and healthy control subjects (n = 18; aged 21-40 years) oscillatory brain activity was recorded using magnetoencephalography during a visuo-spatial attention task. Subjects had to anticipate a target with unpredictable timing and respond by pressing a button. Preparing a motor response, the ADHD group failed to increase hemispheric μ lateralization with relatively higher μ power in sensorimotor regions not engaged in the task, as the controls did (F 1,33 = 8.70, p = 0.006). Moreover, the ADHD group pre-response μ lateralization not only correlated positively with accuracy (r s = 0.64, p = 0.0052) and negatively with intra-individual reaction time variability (r s = -0.52, p = 0.033), but it also correlated negatively with the score on an ADHD rating scale (r s = -0.53, p = 0.028). We suggest that ADHD is associated with an inability to sufficiently inhibit task-irrelevant sensorimotor areas by means of modulating μ oscillatory activity. This could explain disruptive motor activity in ADHD. These results provide further evidence that impaired modulation of α band oscillations is involved in the pathogenesis of ADHD.

No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs

Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.

Evaluation of the Relationship between Brain-Derived Neurotropic Factor Levels and the Stroop Interference Effect in Children with Attention-Deficit Hyperactivity Disorder.

Brain-derived neurotropic factor (BDNF) has been suggested to play a role in the pathogenesis of attention-deficit hyperactivity disorder (ADHD). In addition, impairment in executive functions has been reported in children with ADHD. This study investigated the presence of a relationship between Stroop test scores and BDNF levels in children with ADHD. The study was conducted in the Department of Child Psychiatry at Dicle University. The study included 49 children between 6 and 15 years of age (M/F: 42/7), who were diagnosed with ADHD according to DSM-IV, and who did not receive previous therapy. Similar in terms of age and gender to the ADHD group, 40 children were selected in the control group. The Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version was administered to all participants. Parents and teachers were administered Turgay DSM-IV-based Child and Adolescent Behavior Disorders Screening and Rating Scale to measure symptom severity in children with ADHD. Children with ADHD underwent the Stroop test. BDNF levels were evaluated in serum by ELISA. The ADHD and control groups did not differ in terms of BDNF levels. BDNF levels did not differ between ADHD subtypes. There was also no relationship between the Stroop test interference scores and BDNF levels. The findings of the present study are in line with those in studies that demonstrated no significant role of BDNF in the pathogenesis of ADHD.

P.1.a.018 - Gene expression in the brain of adult rats with behavioural alterations caused by neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin

Attention deficit hyperactivity disorder (ADHD) is much more frequent in males than females, so several genes on the X chromosome (e.g., MAOA and MAOB) have been pursued as candidates for influencing risk for the disorder. HTR2C is also located on the X chromosome. In the current study, we examined the relationship between the C-759T and G-697C polymorphisms of HTR2C and ADHD in 488 Han Chinese families. Transmission Disequilibrium Test (TDT) analysis showed that the −759C allele, the −697G allele, and haplotype −759C/−697G were significantly over-transmitted to affected probands, while haplotypes −759C/−697C and −759T/−697C were under-transmitted. When families were divided into three subtypes according to the diagnosis of probands, the −697G allele and haplotype −759C/−697G were significantly over transmitted to ADHD-C probands, while haplotype −759T/−697C was under-transmitted to these individuals; however, no biased transmission of any allele or haplotype was observed for probands with ADHD-I, suggesting that different subtypes of ADHD have different genetic influences. Our findings highlight the need to explore the role of 5-HT2C receptor dysfunction in the pathogenesis of ADHD.

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits.

Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N=592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p=0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p=0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism Is a Risk Factor for Attention-Deficit Hyperactivity Disorder in a Turkish Sample

ObjectiveAttention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that negatively affects different areas of life. We aimed to evaluate the associations between the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) and ADHD and to assess the effect of the BDNF polymorphism on the neurocognitive profile and clinical symptomatology in ADHD.MethodsTwo hundred one ADHD cases and 99 typically developing subjects (TD) between the ages of 8 and 15 years were involved in the study. All subjects were evaluated using a complete neuropsychological battery, Child Behavior Checklist, the Teacher's Report Form (TRF) and the DSM-IV Disruptive Behavior Disorders Rating Scale-teacher and parent forms.ResultsThe GG genotype was significantly more frequent in the patients with ADHD than in the TD controls, and the GG genotype was also significantly more frequent in the ADHD-combined (ADHD-C) subtype patients than in the TDs. However, there were no significant associations of the BDNF polymorphism with the ADHD subtypes or neurocognitive profiles of the patients. The teacher-assessed hyperactivity and inattention symptom count and the total score were higher, and the appropriately behaving subtest score of the TRF was lower in the GG genotypes than in the GA and AA (i.e., the A-containing) genotypes.ConclusionWe found a positive association between the BDNF gene Val66Met polymorphism and ADHD, and this association was observed specifically in the ADHD-C subtype and not the ADHD-predominantly inattentive subtype. Our findings support that the Val66Met polymorphism of BDNF gene might be involved in the pathogenesis of ADHD. Furthermore Val66Met polymorphism of BDNF gene may be more closely associated with hyperactivity rather than inattention.

Contribution of animal models to contemporary understanding of Attention Deficit Hyperactivity Disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD aetiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. However, such evaluation is important, given the resource consumption and ethical concerns incurred by animal use. Accordingly, we used the citation tracking facility within Web of Science to locate original research performed on animal models related to ADHD, prior to 2010. Human medical papers citing those animal studies were carefully analyzed by two independent raters to evaluate the contribution of the animal to the human studies. 211 publications describing relevant animal studies were located. Approximately half (3,342) of their 6,406 citations were by other animal studies. 446 human medical papers cited 121 of these 211 animal studies, a total of 500 times. 254 of these 446 papers were human studies of ADHD. However, only eight animal papers (cited 10 times) were relevant to the hypothesis of the human medical study in question. Three of these eight papers described results from both human and animal studies, but their citations solely referred to the human data. Five animal research papers were relevant to the hypotheses of the applicable human medical papers. Citation analysis indicates that animal research has contributed very little to contemporary understanding of ADHD. To ensure optimal allocation of Research & Development funds targeting this disease the contribution of other research methods should be similarly evaluated.

Low serum sphingolipids in children with attention deficit-hyperactivity disorder.

Background: Attention deficit-hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric condition in childhood. ADHD is a multifactorial trait with a strong genetic component. One neurodevelopmental hypothesis is that ADHD is associated with a lag in brain maturation. Sphingolipids are essential for brain development and neuronal functioning, but their role in ADHD pathogenesis is unexplored. We hypothesized that serum sphingolipid levels distinguish ADHD patients from unaffected subjects.Methods: We characterized serum sphingolipid profiles of ADHD patients and two control groups: non-affected relatives and non-affected subjects without a family history of ADHD. Sphingolipids were measured by LC-MS/MS in 77 participants (28 ADHD patients, 28 related controls, and 21 unrelated controls). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). Diagnostic criteria were assessed by two independent observers. Groups were compared by parametrical statistics.Results: Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20–30% relative reductions. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity and 78% specificity.Conclusions: Our results showed lower levels of all major serum sphingomyelins in ADHD. These findings may reflect brain maturation and affect neuro-functional pathways characteristic for ADHD.