Role of neurotrophic factors in attention deficit hyperactivity disorder

Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD.     

注意缺陷多动障碍儿童肠道菌群特点及与行为问题的相关性研究

分析注意缺陷多动障碍（ADHD）儿童肠道菌群特点与行为问题的相关性。

选取2022年1月到2023年5月我院收治的96例ADHD患儿和健康体检的96例儿童,分别作为研究组和对照组。对所有儿童粪便样本进行宏基因组测序并分析肠道菌群特点。采用Conners儿童行为问卷－家长版（PSQ）评估两组儿童的行为。采用Pearson相关性分析肠道菌群分布与行为问题的相关性。

研究组患儿肠道菌群α−多样性低于对照组,肠杆菌属、气味杆菌属和枸橼酸杆菌属相对丰度均高于对照组,韦荣球菌属、拟杆菌属、双歧杆菌属和普氏栖粪杆菌相对丰度均低于对照组,差异均具有统计学意义（P＜0.05）。研究组患儿Conners PSQ问卷评分高于对照组（P＜0.05）。研究组患儿Conners PSQ问卷各因子评分与肠道肠杆菌属、气味杆菌属和枸橼酸杆菌属均呈正相关（P＜0.05）,与韦荣球菌属、拟杆菌属、双歧杆菌属和普氏栖粪杆菌均呈负相关（P＜0.05）。

ADHD儿童肠道菌群构成与健康儿童不同,不同肠道菌群与患儿行为问题有相关性。

     

Increased oxidative stress in children with attention deficit hyperactivity disorder

Objectives: The purpose of this study was to investigate oxidative stress in children with attention deficit hyperactivity disorder (ADHD).

Methods: Total oxidant status (TOS), total antioxidant status (TAS), paraxonase-1 (PON-1) and arylesterase (ARE) activity were measured in 76 children (44 boys, 32 girls) diagnosed with ADHD according to the DSM-IV and 78 healthy children (46 boys, 32 girls).

Results: Age and sex were similar between the groups (P?>?0.05). TOS and the oxidative stress index (OSI) were higher in the patient group than the control group (P?<?0.001). PON-1 (P?=?0.002), ARE (P?=?0.010) activity and TAS (P?<?0.001) were lower in the patient group than the control group.

Discussion: We found decreased PON-1, ARE activity and TAS, and increased TOS and OSI in children with ADHD. Our study showed that there is significantly increased oxidative stress in children with ADHD.     

Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation

Current understanding of the underlying molecular network and mechanism for attention-deficit hyperactivity disorder (ADHD) is lacking and incomplete. Previous studies suggest that genomic structural variations play an important role in the pathogenesis of ADHD. For effective modeling, deep learning approaches have become a method of choice, with ability to predict the impact of genetic variations involving complicated mechanisms. In this study, we examined copy number variation in whole genome sequencing from 116 African Americans ADHD children and 408 African American controls. We divided the human genome into 150 regions, and the variation intensity in each region was applied as feature vectors for deep learning modeling to classify ADHD patients. The accuracy of deep learning for predicting ADHD diagnosis is consistently around 78% in a two-fold shuffle test, compared with ∼50% by traditional k-mean clustering methods. Additional whole genome sequencing data from 351 European Americans children, including 89 ADHD cases and 262 controls, were applied as independent validation using feature vectors obtained from the African American ethnicity analysis. The accuracy of ADHD labeling was lower in this setting (∼70–75%) but still above the results from traditional methods. The regions with highest weight overlapped with the previously reported ADHD-associated copy number variation regions, including genes such as GRM1 and GRM8, key drivers of metabotropic glutamate receptor signaling. A notable discovery is that structural variations in non-coding genomic (intronic/intergenic) regions show prediction weights that can be as high as prediction weight from variations in coding regions, results that were unexpected.     

Diagnosing and treating attention-deficit/hyperactivity disorder in adults

Adult attention deficit/hyperactivity disorder (ADHD) is a valid and impairing psychiatric disorder. In this article, we review the diagnosis of ADHD in adults, focusing on symptom presentation differences between pediatric and adult ADHD as well as the importance of assessing functional impairments. Differentiating ADHD from other clinical disorders is often the most difficult part of making an ADHD diagnosis in adults. Psychiatric comorbidities are also described and discussed as potential impact factors upon not only diagnosing ADHD but also treatment of adult ADHD. Especially in those adults with psychiatric comorbidities, treatments need to be multimodal and include both pharmacotherapy and psychosocial interventions.     

CDH13 is associated with working memory performance in attention deficit/hyperactivity disorder

Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.     

LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Latrophilin 3 (LPHN3) is a brain‐specific member of the G‐protein coupled receptor family associated to both attention‐deficit/hyperactivity disorder (ADHD) genetic susceptibility and methylphenidate (MPH) pharmacogenetics. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of this study was to evaluate the role of LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetic study, 172 children with ADHD were investigated. The primary outcome measure was the parent‐rated Swanson, Nolan and Pelham Scale – version IV applied at baseline, first and third months of treatment with MPH. The results reported herein suggest the CGC haplotype derived from single nucleotide polymorphisms (SNPs) rs6813183, rs1355368 and rs734644 as an ADHD risk haplotype (P = 0.02, OR = 1.46). Although non‐significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (P = 0.03, OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a nominally significant interaction with treatment over time (P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD.     

Circadian pattern of motor activity in adults with attention-deficit/hyperactivity disorder

This study aims to describe the 24-hour activity rhythm in adults with attention-deficit/hyperactivity disorder (ADHD). A total of 18 ADHD patients and 37 healthy controls (HCs) wore an actigraph for 7 days. ADHD patients showed higher motor activity than HCs at 4:00, 6:00, 15:00 and 16:00 hour. Within the theoretical framework of the two-process model of sleep regulation, the observed data may be explained by lower homeostatic sleep pressure in ADHD. This could lead to an increase in motor activity in the second half of the night, when sleep need decreases more rapidly, and in the first half of the afternoon, when patients do not experience the typical post-lunch dip.     

Neurofeedback treatment for attention-deficit/hyperactivity disorder in children: a comparison with methylphenidate

Clinical trials have suggested that neurofeedback may be efficient in treating attention-deficit/hyperactivity disorder (ADHD). We compared the effects of a 3-month electroencephalographic feedback program providing reinforcement contingent on the production of cortical sensorimotor rhythm (12–15 Hz) and beta1 activity (15–18 Hz) with stimulant medication. Participants were N = 34 children aged 8–12 years, 22 of which were assigned to the neurofeedback group and 12 to the methylphenidate group according to their parents' preference. Both neurofeedback and methylphenidate were associated with improvements on all subscales of the Test of Variables of Attention, and on the speed and accuracy measures of the d2 Attention Endurance Test. Furthermore, behaviors related to the disorder were rated as significantly reduced in both groups by both teachers and parents on the IOWA-Conners Behavior Rating Scale. These findings suggest that neurofeedback was efficient in improving some of the behavioral concomitants of ADHD in children whose parents favored a nonpharmacological treatment.     

miRNA profiling in the hippocampus of attention-deficit/hyperactivity disorder rats

Attention-deficit/hyperactivity disorder (ADHD) is characterized by attention deficit, hyperactivity, impulsivity, and learning and memory impairment. Although the pathogenesis of learning and memory impairment is still unknown, some studies have suggested an association with hippocampus dysfunction. We aimed to explore the role of miRNAs in the learning and memory impairments observed in ADHD. Differentially expressed hippocampal micro-ribonucleic acids (miRNAs) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were detected on an Illumina HiSeq. 2000 genome analyzer. A total of 25 differentially expressed miRNAs (fold-change ≥ 2 and P-value < 0.05) were identified. The target genes of these differentially expressed miRNAs were predicted using online tools (TargetScan and miRDB). Gene ontology and pathway analysis of the predicted target genes were carried out to assess their putative biological functions. Meanwhile, quantitative real-time PCR was used to validate the HiSeq results, revealing that three miRNAs (miR-1-b, miR-741-3p, and miR-206-3p) were upregulated and four (miR-182, miR-471-5p, miR-183-5p, and miR-211-5p) were downregulated in the SHR group compared with the WKY group. In addition, we confirmed that Dyrk1a is regulated by miR-211-5p. These results help us understand the contribution of miRNAs in the hippocampus to ADHD and provide new insights into the pathogenesis of this condition.     

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.     

注意缺陷多动障碍共患阅读障碍：认知-脑-基因的多维度研究进展

注意缺陷多动障碍(attention-deficit/hyperactivity disorder,ADHD)和发展性阅读障碍(developmental dyslexia,DD)是两种常见的神经发育性障碍,二者共患的比率高达25%～48%.本文拟从认知-脑-基因等多个维度对ADHD共患DD的研究进展进行综述. ADHD和DD共患的共同认知损害可能是加工速度缺陷,其作为内表型能够很好地帮助解释遗传因素如何通过影响认知功能进而导致出现ADHD共患DD的临床表型.而国内对ADHD共患DD的研究较少,已有的多项研究仅关注ADHD伴学习障碍,但缺乏标准的DD临床诊断标准.本文指出了统一诊断标准、结合多学科研究以及未来个体化训练的必要性.     

Testing candidate genes for attention-deficit/hyperactivity disorder in fruit flies using a high throughput assay for complex behavior

Fruit flies are important model organisms for functional testing of candidate genes in multiple disciplines, including the study of human diseases. Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim was to investigate the impact of disruption of 14 candidate genes for human attention-deficit/hyperactivity disorder (ADHD) on fly behavior. By obtaining a range of correlated measures describing the space of variables for behavioral activity we show, that some mutants display similar phenotypic responses, and furthermore, that the genes disrupted in those mutants had common molecular functions; namely processes related to cGMP activity, cation channels and serotonin receptors. All but one of the candidate genes resulted in aberrant behavioral activity, suggesting involvement of these genes in behavioral activity in fruit flies. Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans.     

Interplay between stress response genes associated with attention‐deficit hyperactivity disorder and brain volume

The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention‐deficit hyperactivity disorder (ADHD). The serotonin transporter (5‐HTT) gene polymorphism 5‐HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5‐HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5‐HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non‐carriers. This gene–environment interaction was significantly stronger for 5‐HTTLPR L‐allele homozygotes than for S‐allele carriers. These two‐ and three‐way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5‐HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic–pituitary–adrenal axis activity in ADHD.     

Attention‐deficit/hyperactivity disorder as a risk factor for cardiovascular diseases: a nationwide population‐based cohort study

Accumulating evidence suggests a higher risk for cardiovascular diseases among individuals with mental disorders, but very little is known about the risk for overall and specific groups of cardiovascular diseases in people with attention‐deficit/hyperactivity disorder (ADHD). To fill this knowledge gap, we investigated the prospective associations between ADHD and a wide range of cardiovascular diseases in adults. In a nationwide population‐based cohort study, we identified 5,389,519 adults born between 1941 and 1983, without pre‐existing cardiovascular diseases, from Swedish registers. The study period was from January 1, 2001 to December 31, 2013. Incident cardiovascular disease events were identified according to ICD codes. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression model, with ADHD as a time‐varying exposure. After an average 11.80 years of follow‐up, 38.05% of individuals with ADHD versus 23.57% of those without ADHD had at least one diagnosis of cardiovascular disease (p<0.0001). ADHD was significantly associated with increased risk of any cardiovascular disease (HR=2.05, 95% CI: 1.98‐2.13) after adjusting for sex and year of birth. Further adjustments for education level, birth country, type 2 diabetes mellitus, obesity, dyslipidemia, sleep problems and heavy smoking attenuated the association, which however remained significant (HR=1.84, 95% CI: 1.77‐1.91). Further adjustment for psychiatric comorbidities attenuated but could not fully explain the association (HR=1.65, 95% CI: 1.59‐1.71). The strongest associations were found for cardiac arrest (HR=2.28, 95% CI: 1.81‐2.87), hemorrhagic stroke (HR=2.16, 95% CI: 1.68‐2.77), and peripheral vascular disease/arteriosclerosis (HR=2.05, 95% CI: 1.76‐2.38). Stronger associations were observed in males and younger adults, while comparable associations were found among individuals with or without psychotropic medications and family history of cardiovascular diseases. These data suggest that ADHD is an independent risk factor for a wide range of cardiovascular diseases. They highlight the importance of carefully monitoring cardiovascular health and developing age‐appropriate and individualized strategies to reduce the cardiovascular risk in individuals with ADHD.