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Background and Objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy., Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 ( c9orf72 ), progranulin ( GRN ), or microtubule-associated protein tau ( MAPT ) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms., Results: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness., Discussion: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Objective: Alcohol withdrawal syndrome (AWS) is a complex condition associated with alcohol use disorder (AUD), characterized by significant variations in symptom severity among patients. The psychological and emotional symptoms accompanying AWS significantly contribute to withdrawal distress and relapse risk. Despite the importance of neural adaptation processes in AWS, limited genetic investigations have been conducted. This study primarily focuses on exploring the single and interaction effects of single-nucleotide polymorphisms in the ANK3 and ZNF804A genes on anxiety and aggression severity manifested in AWS. By examining genetic associations with withdrawal-related psychopathology, we ultimately aim to advance understanding the genetic underpinnings that modulate AWS severity., Methods: The study involved 449 male patients diagnosed with alcohol use disorder. The Self-Rating Anxiety Scale (SAS) and Buss-Perry Aggression Questionnaire (BPAQ) were used to assess emotional and behavioral symptoms related to AWS. Genomic DNA was extracted from peripheral blood, and genotyping was performed using PCR., Results: Single-gene analysis revealed that naturally occurring allelic variants in ANK3 rs10994336 (CC homozygous vs. T allele carriers) were associated with mood and behavioral symptoms related to AWS. Furthermore, the interaction between ANK3 and ZNF804A was significantly associated with the severity of psychiatric symptoms related to AWS, as indicated by MANOVA. Two-way ANOVA further demonstrated a significant interaction effect between ANK3 rs10994336 and ZNF804A rs7597593 on anxiety, physical aggression, verbal aggression, anger, and hostility. Hierarchical regression analyses confirmed these findings. Additionally, simple effects analysis and multiple comparisons revealed that carriers of the ANK3 rs10994336 T allele experienced more severe AWS, while the ZNF804A rs7597593 T allele appeared to provide protection against the risk associated with the ANK3 rs10994336 mutation., Conclusion: This study highlights the gene-gene interaction between ANK3 and ZNF804A, which plays a crucial role in modulating emotional and behavioral symptoms related to AWS. The ANK3 rs10994336 T allele is identified as a risk allele, while the ZNF804A rs7597593 T allele offers protection against the risk associated with the ANK3 rs10994336 mutation. These findings provide initial support for gene-gene interactions as an explanation for psychiatric risk, offering valuable insights into the pathophysiological mechanisms involved in AWS., (© 2024. The Author(s).)

Background and Objectives: SOD1 variants in patients with amyotrophic lateral sclerosis (ALS) have been associated with peculiar clinical features and disease progression but rarely with cognitive and behavioral impairment. This study aims at describing the features of frontotemporal syndromes in patients with ALS carrying SOD1 variants., Methods: Italian patients with ALS were consecutively enrolled between 2012 and 2020 at our Motor Neuron Disease Center. All underwent clinical assessment, extensive neurophysiologic test battery for the evaluation of cognitive functions and behavior, and targeted next-generation sequencing of SOD1 , FUS , TARDBP , VCP , PFN1 , TUBA4A , OPTN , SQSTM1 , UBQLN2 , and C9orf72 genes. Neuropsychological profiles of SOD1 + patients (SOD1+) were compared with those with no gene variants (SOD1-). To this aim, the occurrence of cognitive and behavioral impairment defined according to the current guidelines, the number of pathologic test performances based on Italian normative values, and scores of the Frontal Behavioral Inventory were collected., Results: Among 288 patients consecutively examined, we identified 8 known pathogenic SOD1 variants and one variant of uncertain significance (p.Ser26Asn) not previously described in 14 patients with ALS belonging to 11 families. The clinical phenotypes were mainly characterized by predominant lower motor neuron involvement with onset at the lower limbs, and one patient had bulbar onset. SOD1+ patients (n = 14) were compared with SOD1- patients (N = 274). SOD1+ patients were younger than SOD1-, and both groups had similar functional motor disabilities and disease duration. Based on the overall neuropsychological findings, the percentage of SOD1+ and SOD1- patients with altered profiles were approximately 60%. However, behavioral impairment defined by the Strong criteria, and most commonly featuring with irritability and mental rigidity, was more frequent in SOD1+ than SOD1- patients and mainly associated with variants in exon 5. Conversely, cognitive impairment was mainly found in SOD1- patients., Discussion: Our findings from a large cohort of deeply phenotyped patients with ALS demonstrated that behavioral involvement is more common than previously thought among patients harboring SOD1 variants and that it is independent from patients' age and disease stage. These findings could be relevant for the assessment of clinical trial outcomes and disease management., (© 2022 American Academy of Neurology.)

Objective: This long-term retrospective follow-up study aimed to address the knowledge gap between prenatal diagnosis of complete isolated Agenesis of Corpus Callosum (cACC) at fetal MRI and postnatal neurodevelopmental outcome to improve prenatal counseling for parents., Methods: Data on fetuses with isolated cACC from a single-center MRI database built up in two decades were considered. Detailed postnatal clinical, neuropsychological evaluations were performed and descriptions of available neuroradiological and genetic data were provided., Results: Following a detailed neuropsychological evaluation and a long-term follow-up, the subsequent results emerged: 38 school-aged children (older than 6 years) of 50 (aged 2.5-15 years) showed normal intellectual functions (50%), intellectual disability (21%), and borderline intelligence quotient (29%). Deficits in motor functions (58%), executive functions (37%), language (61%), memory abilities (58%), and academic performances (53%) were found. Twenty-one percent of participants showed behavioral difficulties. Almost half of the participants underwent rehabilitation. Additional findings (21%) were detected at postnatal brain MRI, and a significant association between additional findings at postnatal imaging and abnormal neurodevelopmental outcome was observed., Interpretations: This study supports the view that children with prenatal diagnosis of isolated cACC may present with several degrees of neurologic and neuropsychological impairment which become more evident only in their second decade of life. Postnatal MRI and detailed genetic analysis may add crucial information to prenatal data and substantially influence final judgment on the outcome and orient clinical management and counseling., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Accumulating research addressed epigenetic modifications and their role on behavioral phenotypes. We recently proposed to study methylation dynamics of two CpG motifs within the 5'-UTR of dopamine transporter (DAT) gene. Starting from a normative population sample of young adults, we selected three sub-groups based on their prevalent symptoms: subjects were assigned to Internalizing, Externalizing and Low-risk sub-groups according to elevated scores in specific phenotypic scales. Using a new approach, we calculated three independent matrixes of cross-correlation between CpG methylation levels, one within each phenotypic sub-group, to determine in which dynamics did the sub-groups differ. We found specific cross-correlation patterns in Externalizing (CpG1, 2 and 3, opposite to the methylation at CpG6) and Internalizing individuals (CpG1 methylation opposite to CpG2, 3 and 6), while Low-risk individuals could follow both trends. The aim of our study was to look for a specific DAT methylation pattern, providing a biomarker that allows early identification of the risk for psycho-pathological deviance., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Neurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of neuropsychiatric disorders, we assessed multiple domains of behavioral phenotypes in Nrgn KO mice using a comprehensive behavioral test battery including tests of homecage locomotor activity and nesting behavior., Methods: Adult Nrgn KO mice (28-54 weeks old) were subjected to a battery of comprehensive behavioral tests, which examined general health, nesting behavior, neurological characteristics, motor function, pain sensitivity, locomotor activity, anxiety-like behavior, social behavior, sensorimotor gating, depression-like behavior, and working memory., Results: The Nrgn KO mice displayed a pronounced decrease in nesting behavior, impaired motor function, and elevated pain sensitivity. While the Nrgn KO mice showed increased locomotor activity in the open field test, these mice did not show hyperactivity in a familiar environment as measured in the homecage locomotor activity test. The Nrgn KO mice exhibited a decreased number of transitions in the light-dark transition test and decreased stay time in the center of the open field test, which is consistent with previous reports of increased anxiety-like behavior. Interestingly, however, these mice stayed on open arms significantly longer than wild-type mice in the elevated plus maze. Consistent with previous studies, the mutant mice exhibited decreased prepulse inhibition, impaired working memory, and decreased sociability., Conclusions: In the current study, we identified behavioral phenotypes of Nrgn KO mice that mimic some of the typical symptoms of neuropsychiatric diseases, including impaired executive function, motor dysfunction, and altered anxiety. Most behavioral phenotypes that had been previously identified, such as hyperlocomotor activity, impaired sociability, tendency for working memory deficiency, and altered sensorimotor gating, were reproduced in the present study. Collectively, the behavioral phenotypes of Nrgn KO mice detected in the present study indicate that Nrgn KO mice are a valuable animal model that recapitulates a variety of symptoms of neuropsychiatric disorders, such as schizophrenia, ADHD, and Alzheimer's disease., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.)

Objective: To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome., Methods: A Next Generation Sequencing - based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis)., Results: Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes., Conclusions: Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions., (Copyright © 2021. Published by Elsevier Ltd.)

Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll-HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid-adult onset (30-59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid-adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one-year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one-year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The dysregulation of the inflammatory response, including pro-inflammatory molecules, produces neuropsychiatric symptoms and depression-like behavior, including withdrawal from the physical and social environment. Genetic variants that enhance immune reactivity may thus increase inflammatory and withdrawn reactions to stress. Here we investigated a functional polymorphism of Interferon Gamma gene (IFNG +874 T > A, rs2430561) as moderator of the relationship between mothers' distress exposure and children's withdrawn behavior at preschool age. Participants were 198 Portuguese preschool children (mean age = 57.98 months). Exposure to mother's distress was assessed using the Brief Symptom Inventory, and withdrawn behavior with the Caregiver Teacher Report Form. All children provided saliva samples for genotyping. Contrary to expecations based on prior work, the rs2430561 AA genotype-not the T variant-interacted with (high levels of) mothers' distress exposure, to increase children's withdrawn behavior. No significant main effects were detected. The polymorphism in Interferon Gamma gene showed specific environmental stressor-dependent effects on withdrawn behavior during childhood, ones which are interpreted in light of the "behavioral immune system" hypothesis, and which proved inconsistent with diathesis-stress thinking., (© 2020 Wiley Periodicals, Inc.)

Genetic predisposition of social sensitivity might affect vulnerability to develop psychopathology after early life stress exposure. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in developing internalizing symptoms at ages 5-6 and 11-12. In the Amsterdam-Born-Children-and-their-Development (ABCD) study, a large observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week by a self-report questionnaire. Internalizing symptoms at age 5-6 were assessed by maternal report (N = 969) and internalizing symptoms at age 11-12 were assessed by self-report (N = 750). Data on oxytocin receptor polymorphisms rs53576 and rs2268498 and oxytocin polymorphisms rs2740210 and rs4813627 were collected. If the child was carrier of rs2740210 CA/AA polymorphism, exposure to maternal verbally aggressive behavior (10.6%) was positively associated with general anxiety at age 5-6 and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.015, respectively). If the child was carrier of rs4813627 GG (wild type), exposure to maternal verbally aggressive behavior was negatively associated with anxiety sensitivity and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.022, respectively). After exposure to maternal verbally aggressive behavior in early infancy, oxytocin polymorphisms may partly determine a child's vulnerability to internalizing symptoms.

Importance: Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits., Objective: To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders., Design, Setting, and Participants: This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019., Exposures: Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI)., Main Outcomes and Measures: Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater., Results: The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (β estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (β, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δβ, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δβ, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δβ, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δβ, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δβ, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008)., Conclusions and Relevance: Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

Background: Autism spectrum disorder (ASD) affects approximately one in 59 children. Variants in the activity-dependent neuroprotector homeobox ADNP (OMIM #611386) gene may be one of the most common single-gene causes of syndromic ASD. Most patients diagnosed with ADNP syndrome have ASD as a comorbidity, and all patients have mild-to-severe intellectual disability., Methods/case Report: We present a case report of a patient diagnosed with ADNP syndrome at 2.5 years of age. The patient has many of the key features of the syndrome, including ASD, global developmental delay, behavioral problems, congenital heart defect, early tooth eruption, and vision problems. The patient's initial presentation included congenital diaphragmatic hernia (CDH), which has not been previously reported in this condition., Results: The patient exhibited frequent behavioral outbursts and was initiated on antipsychotic medication with near-complete resolution of symptoms allowing her to engage more fully in early intervention therapies leading to progress in language acquisition., Conclusion: This short report provides guidance for antipsychotic medication dosing to improve early intervention outcomes. This is the first report of CDH in this syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objective: The main purpose of this article is to demonstrate the co-occurrence of Axenfeld-Rieger anomaly and neuropsychiatric problems as clinical signs of genetically determined cerebral small vessel disease in two patients., Case Study: We report on two adolescent individuals with ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) presenting with neuropsychiatric symptoms. Both patients underwent cerebral magnetic resonance imaging showing white matter T2-hyperintensities involving different brain regions, suspective of cerebral small vessel disease. Genetic analysis revealed pathogenic mutations in the FOXC1 gene (patient 1) and the COL4A1 gene (patient 2), respectively., Conclusion: We report on the co-occurrence of ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) and neuropsychiatric symptoms as clinical signs of genetically determined cerebral small vessel disease in two patients. In both patients, the cerebral lesions involved the frontotemporal regions, brain regions that control social behavior as well as executive and cognitive function, highlighting the fact that neuropsychiatric symptoms may be early clinical presentations of cerebral small vessel disease. We further provide a review of monogenic causes of pediatric cerebral small vessel disease, emphasizing the links to childhood-onset neuropsychiatric disease., Competing Interests: Dr. Ziegler reports personal fees from Biogen, personal fees from Avexis, and personal fees from PTC, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children worldwide, and also the recognition of its persistence into adulthood is increasing. While ADHD in childhood is highly heritable and mostly driven by familial factors, during adulthood it appears to show a lower heritability, even if there is not total agreement on this yet. This disorder often co-occurs with many other conditions, which also vary across the different stages of development, and several studies have used the twin design to investigate these comorbidities, giving valuable insights into the origins of the observed co-occurrence. This review aims to summarize the main results of twin research, according to the following domains: individual traits, cognitive impairment, behavioral manifestations, clinical conditions and psychosocial risk factors. Individual features seem to play a role in this symptomatology and include personality traits such as negative emotionality, personality disorders and temperamental dimensions with a predominance of novelty seeking. At a lower level, ADHD is associated with both functional and anatomic brain characteristics. ADHD is also associated with some forms of cognitive impairment, such as sluggish cognitive tempo, and learning disabilities, with a specific predisposition to reading disability. In addition, ADHD is strongly associated with externalizing disorders such as conduct disorder and oppositional defiant disorder, and some behavioral outcomes, particularly substance use and abuse both in adolescence and adulthood. Moreover, ADHD symptoms often overlap with other psychological disorders, namely affective and internalizing disorders, as well as autism spectrum disorder and autistic-like traits in a wider sense. Notably, a genetic overlap has been found between asthma and ADHD, particularly with respect to hyperactivity/impulsivity dimensions. ADHD also appears to represent a risk factor for disordered eating, and, more specifically, for binge eating and bulimia nervosa. Finally, among psychosocial factors, an association has been proposed between childhood maltreatment and ADHD symptoms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Diverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self-, parent- and teacher-rated measures in childhood and adolescence., Methods: The sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive traits, emotional problems, peer problems, autism traits, hyperactivity, antisocial behaviour, conduct problems and psychopathic tendencies). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for psychiatric disorders to estimate how a general polygenic predisposition to mostly adult psychiatric disorders relates to childhood p., Results: Behaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50%-60%) and manifests consistently across diverse ages and raters. However, residual variation in the common factor models indicates unique contributions as well. Genetic correlations of p components across childhood and adolescence suggest stability over time (49%-78%). A polygenic general psychopathology factor derived from studies of psychiatric disorders consistently predicted a general phenotypic p factor across development (0.3%-0.9%)., Conclusions: Diverse forms of psychopathology generally load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far-reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems., (© 2019 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55-199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours., Methods: This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours., Results: Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning., Conclusions: Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

Posttraumatic stress disorder (PTSD) is associated with wide-spread immune dysregulation; however, little is known about the gene expression differences attributed to each PTSD symptom cluster. This is an important consideration when identifying diagnostic and treatment response markers in highly comorbid populations with mental and physical health conditions that share symptoms. To this aim, we utilized a transcriptome-wide analysis of differential gene expression in peripheral blood by comparing military service members: (1) with vs. without PTSD, (2) with high vs. low PTSD cluster symptom severity, and (3) with improved vs. not improved PTSD symptoms following 4-8 weeks of evidenced-based sleep treatment. Data were analyzed at a ±2.0-fold change magnitude with subsequent gene ontology-based pathway analysis. In participants with PTSD (n = 39), 89 differentially expressed genes were identified, and 94% were upregulated. In participants with high intrusion symptoms (n = 22), 1040 differentially expressed genes were identified, and 98% were upregulated. No differentially expressed genes were identified for the remaining two PTSD symptom clusters. Ten genes (C5orf24, RBAK, CREBZF, CD69, PMAIP1, AGL, ZNF644, ANKRD13C, ESCO1, and ZCCHC10) were upregulated in participants with PTSD and high intrusion symptoms at baseline and downregulated in participants with improved PTSD symptoms following treatment. Pathway analysis identified upregulated immune response systems and metabolic networks with a NF-kB hub, which were downregulated with symptom reduction. Molecular biomarkers implicated in intrusion symptoms and PTSD symptom improvement may inform the development of therapeutic targets for precise treatment of PTSD., (Published by Elsevier Inc.)

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in ether lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that ether lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of ether lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder., (© The Author(s) 2019. Published by Oxford University Press.)

Aging is a natural process that internal gene control and external stimuli mediate. Clinical data pointed out that homozygotic or heterozygotic mutation in the pyrroline-5-carboxylate reductase 1 ( PYCR1 ) gene in humans caused cutis laxa (ARCL) disease, with progeroid appearance, lax and wrinkled skin, joint laxity, osteopenia, and mental retardation phenotypes. In this study, we aimed to generate pycr1 knockout (KO) zebrafish and carried out biochemical characterizations and behavior analyses. Marked apoptosis and senescence were detected in pycr1 KO zebrafish, which started from embryos/larvae stage. Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents, lowered energy, and diminished superoxide dismutase (SOD) and telomerase activity when compared to the wild type fish, which suggested the pycr1 KO fish may have dysfunction in mitochondria. The pycr1 KO fish were viable; however, displayed progeria-like phenotype from the 4 months old and reach 50% mortality around six months old. In adult stage, we found that pycr1 KO fish showed reduced locomotion activity, aggression, predator avoidance, social interaction interest, as well as dysregulated color preference and circadian rhythm. In summary, we have identified multiple behavioral alterations in a novel fish model for aging with pycr1 gene loss-of-function by behavioral tests. This animal model may not only provide a unique vertebrate model to screen potential anti-aging drugs in the future, but also be an excellent in vivo model towards a better understanding of the corresponding behavioral alterations that accompany aging.

Little is known about the exact genes that confer vulnerability or resilience to environmental stressors during early neurodevelopment. Partial genetic deletion of neuregulin 1 (Nrg1) moderates the neurobehavioural effects of stressors applied in adolescence and adulthood, however, no study has yet examined its impact on prenatal stress. Here we examined whether Nrg1 deficiency in mice modulated the impact of prenatal stress on various behaviours in adulthood. Male heterozygous Nrg1 mice were mated with wild-type female mice who then underwent daily restraint stress from days 13 to 19 of gestation. Surprisingly, prenatal stress had overall beneficial effects by facilitating sensorimotor gating, increasing sociability, decreasing depressive-like behaviour, and improving spatial memory in adulthood. Such benefits were not due to any increase in maternal care, as prenatal stress decreased nurturing of the offspring. Nrg1 deficiency negated the beneficial behavioural effects of prenatal stress on all measures except sociability. However, Nrg1 deficiency interacted with prenatal stress to trigger locomotor hyperactivity. Nrg1 deficiency, prenatal stress or their combination failed to alter acute stress-induced plasma corticosterone concentrations. Collectively these results demonstrate that Nrg1 deficiency moderates the effects of prenatal stress on adult behaviour, but it does so in a complex, domain-specific fashion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Angiotensin-Converting Enzyme (ACE) gene has drawn attention for its possible role in regulating the degradation of β-amyloid (Aβ), yet its role in affecting the cognitive and psychiatric symptoms of Alzheimer`s Disease (AD) patients has yet to be elucidated., Objective: This study aimed to investigate whether the ACE gene acts as a risk factor of Behavioral and Psychological Symptoms of Dementia (BPSD) in the AD population., Methods: The genotyping of ACE and Apolipoprotein E gene with allele ε4(APOEε4) was determined among 360s clinically diagnosed AD patients. Symptoms and severity of BPSD were evaluated annually via Neuropsychiatric Inventory (NPI)., Results: At the base measurement of the first year of patient recruitment, there were no significant contributory risk factors to NPI score. In the two-year follow-up, ACE insertion polymorphism showed a significant risk (adjusted odds ratio=1.65, 95% CI=1.1- 2.5, p=0.019) of progression of NPI total score., Conclusion: ACE gene is involved in aggravating BPSD among AD patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Variants of the DRD2 Taq1A polymorphism, which have been shown to result in functional differences in dopamine D2 receptors (D2R), have been linked to various externalizing outcomes in adults. However, the neurobiological processes that contribute to these associations are not well understood. The current study investigates gene × environment effects on teacher-rated externalizing behaviors and probabilistic decision making in a sample of 333 children (age 9) enrolled in an ongoing longitudinal study. Findings indicate that externalizing behaviors increased as a function of hypoxic exposure only among individuals carrying the A1 (A1+) allele. Results also indicate that willingness to pursue reward under conditions of maximum uncertainty (50% probability) decreased as a function of hypoxic exposure only among A1- individuals. Among A1 carriers, no association between probability decision making and hypoxic exposure emerged. These findings suggest that hypoxia could influence neural development through different biological pathways depending on D2 receptor genotype, and provide insight into the development of individual differences in behavior and decision making., (© 2018 Wiley Periodicals, Inc.)

Background: Childhood emotional and behaviour problems are antecedents for later psychopathology. This study investigated genetic and environmental influences shaping the longitudinal association between childhood emotional and behaviour problems and specific PEs., Method: In a community-based twin sample, parents reported on emotional and behaviour problems when twins were ages 7 and 12 years. At age 16 years, specific PEs were measured using self-reports and parent reports. Structural equation model-fitting was conducted., Results: Childhood emotional and behaviour problems were significantly associated with paranoia, cognitive disorganisation and parent-rated negative symptoms in adolescence (mean r = .15-.38), and to a lesser extent with hallucinations, grandiosity and anhedonia (mean r = .04-.12). Genetic influences on childhood emotional and behaviour problems explained significant proportions of variance in adolescent paranoia (4%), cognitive disorganisation (8%) and parent-rated negative symptoms (3%). Unique environmental influences on childhood emotional and behaviour problems explained ≤1% of variance in PEs. Common environmental influences were only relevant for the relationship between childhood emotional and behaviour problems and parent-rated negative symptoms (explaining 28% of variance) and are partly due to correlated rater effects., Conclusions: Childhood emotional and behaviour problems are significantly, if weakly, associated with adolescent PEs. These associations are driven in part by common genetic influences underlying both emotional and behaviour problems and PEs. However, psychotic experiences in adolescence are largely influenced by genetic and environmental factors that are independent of general childhood emotional and behaviour problems, suggesting they are not merely an extension of childhood emotional and behaviour problems., (© 2017 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Purpose of Review: The rising suicide rate in the USA will not be reversed without improved risk assessment and prevention practices. To date, the best method for clinicians to assess a patient's risk for suicide is screening for past suicide attempts in the patient and their family. However, neuroimaging, genomic, and biochemical studies have generated a body of findings that allow description of an initial heuristic biological model for suicidal behavior that may have predictive value., Recent Findings: We review studies from the past 3 years examining potential biological predictors of suicide attempt behavior. We divide findings into two major categories: (1) structural and functional brain imaging findings and (2) biochemical and genomic findings encompassing several systems, including major neurotransmitters (serotonin, catecholamines, GABA, and glutamate), the hypothalamic pituitary adrenal (HPA) axis, the inflammasome, lipids, and neuroplasticity. The biomarkers that appear promising for assessing suicide risk in clinical settings include indices of serotonergic function, inflammation, neuronal plasticity, and lipids.

Background: Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described., Methods: Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation., Results: Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted., Conclusions: Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To compare the cognitive and psychiatric status of patients with Parkinson's disease related to the G2019S and the R1441G mutations of the LRRK2 gene (LRRK2-PD) and idiopathic Parkinson's disease (iPD) patients., Methods: We examined cognition and psychiatric symptoms in 27 patients with LRRK2-PD (12 G2019S and 15 R1441G) and 27 iPD patients., Results: The groups were similar in age, education, disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale (UPDRS) II-IV; however, the LRRK2-PD showed less impairment on UPDRS-I (2.0 ± 1.7 vs. 4.2 ± 2.8, p = 0.003). The LRRK2-PD presented less frequent subjective cognitive complaints (18.5% vs. 63.0%, p = 0.002), and mild cognitive impairment or dementia (25.9% vs. 59.2%, p = 0.027). They also showed less impairment on scales for general cognition (Mattis dementia rating scale 131.2 ± 10.9 vs. 119 ± 24.0, p = 0.022), episodic verbal memory (Rey's auditory verbal learning test, immediate recall 39.2 ± 9.5 vs. 27.6 ± 12.8 p < 0.001, delayed recall 7.2 ± 3.7 vs. 4.7 ± 4.0 p = 0.022), and the Neuropsychiatric Inventory (9.7 ± 9.2 vs. 20.5 ± 14.3, p = 0.004, significant differences for apathy and hallucinations). The LRRK2-PD subjects were less frequently treated with antipsychotic medication (0% vs. 25.9%, p = 0.010). There were no significant differences between G2019S and R1441G mutation carriers., Conclusions: Mutations of the LRRK2 gene might cause PD associated with less cognitive and neuropsychiatric impairment as compared to iPD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

Objective: Autism spectrum disorder is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, the authors adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for autism spectrum disorder., Method: Linkage analyses using scores from the Social Responsiveness Scale were performed in 590 families from the Autism Genetic Resource Exchange, a largely multiplex autism spectrum disorder cohort. Regional and genomewide association analyses were performed to search for common variants contributing to social responsiveness., Results: Social Responsiveness Scale scores were unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in female offspring. In correlated analyses differing by Social Responsiveness Scale respondent, genomewide significant linkage for social responsiveness was identified at chr8p21.3 (multipoint LOD=4.11; teacher/parent scores) and chr8q24.22 (multipoint LOD=4.54; parent-only scores), respectively. Genomewide or linkage-directed association analyses did not detect common variants contributing to social responsiveness., Conclusions: The sex-differential distributions of Social Responsiveness Scale scores in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to autism spectrum disorder among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as autism spectrum disorder. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of autism spectrum disorder.

Background: Huntington's disease (HD) is a genetically mediated neurodegenerative disorder characterized by presence of involuntary movements, behavioral problems and cognitive dysfunctions. Though few patients with HD may have behavioral symptoms at onset of the disease, studies comparing patients with behavioral symptoms at the onset of HD with those having motor symptoms are sparse., Objective: Objective of this study is to determine the differences in the demographic and genetic characteristics of patients with behavioral symptom at the onset of HD from those with motor symptoms., Methods: A chart review of 92 patients with HD who had attended the neurology outpatient clinics of National Institute of Mental Health and Neurosciences, India was done. Demographic and genetic characteristics of HD patients with onset of the disease with initial behavioral symptoms (HD-iB) were compared with patients with onset of the disease with initial motor symptoms (HD-iM)., Results: The principal findings in our study were (i) higher proportion of patients with HD-iB had a positive family history of HD, (ii) maternal inheritance of HD was more frequent among those with HD-iB, and (iii) There is no significant difference between the CAG repeat length between HD-iB and HD-iM groups., Conclusion: Presence of family history of HD especially inheritance of HD from mother may be associated with behavioral symptoms at the onset of HD. CAG repeat length in patients with HD-iB does not differ from those with HD-iM.

Research on the role of puberty in adolescent psychological development requires attention to the meaning and measurement of pubertal development. Particular questions concern the utility of self-report, the need for complex models to describe pubertal development, the psychological significance of pubertal timing vs. tempo, and sex differences in the nature and psychological significance of pubertal development. We used longitudinal self-report data to model linear and logistic trajectories of pubertal development, and used timing and tempo estimates from these models, and from traditional approaches (age at menarche and time from onset of breast development to menarche), to predict psychological outcomes of internalizing and externalizing behavior problems, and early sexual activity. Participants (738 girls, 781 boys) reported annually from ages 9 through 15 on their pubertal development, and they and their parents reported on their behavior in mid-to-late adolescence and early adulthood. Self-reports of pubertal development provided meaningful data for both boys and girls, producing good trajectories, and estimates of individuals' pubertal timing and tempo. A logistic model best fit the group data. Pubertal timing was estimated to be earlier in the logistic compared to linear model, but linear, logistic, and traditional estimates of pubertal timing correlated highly with each other and similarly with psychological outcomes. Pubertal tempo was not consistently estimated, and associations of tempo with timing and with behavior were model dependent. Advances in modeling facilitate the study of some questions about pubertal development, but assumptions of the models affect their utility in psychological studies., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Multiple behavioral and health outcomes, including internalizing symptoms, may be predicted from prenatal maternal anxiety, depression, or stress. However, not all children are affected, and those that are can be affected in different ways. Here we test the hypothesis that the effects of prenatal anxiety are moderated by genetic variation in the child's brain-derived neurotrophic factor (BDNF) gene, using the Avon Longitudinal Study of Parents and Children population cohort. Internalizing symptoms were assessed from 4 to 13 years of age using the Strengths and Difficulties Questionnaire (n = 8,584); a clinical interview with the adolescents was conducted at age 15 years (n = 4,704). Obstetric and psychosocial risk and postnatal maternal symptoms were included as covariates. Results show that prenatal maternal anxiety predicted internalizing symptoms, including with the diagnostic assessment at 15 years. There was a main effect of two BDNF polymorphisms (rs6265 [val66met] and rs11030104) on internalizing symptoms up to age 13. There was also genetic moderation of the prenatal anxiety effect by different BDNF polymorphisms (rs11030121 and rs7124442), although significant effects were limited to preadolescence. The findings suggest a role for BDNF gene-environment interactions in individual vulnerability to the effects of prenatal anxiety on child internalizing symptoms.

We examined the association between the norepinephrine transporter (SLC6A2) gene and autism spectrum disorder (ASD) in a Korean population. In addition, we investigated which phenotypes of ASD are best attributed to the genotype of SLC6A2. A total of 184 subjects with ASD, their 156 unaffected siblings and both biological parents were recruited through university hospitals. We used the Autism Diagnostic Interview-Revised, the Aberrant Behaviour Checklist (ABC), the Child Behaviour Checklist (CBCL), the Stroop Colour-Word Interference Test and the Wisconsin Card Sorting Test (WCST) as quantitative measures of the ASD phenotypes. The associations between the quantitative measures and specific single-nucleotide polymorphisms (SNPs) were tested with linear regression analyses. We did not find any evidence of the over-transmission of either allele of the 10SLC6A2 SNPs in the DFAM test. At an empirical p value <0.05, findings that were consistent between the linear regression analyses and the QFAM tests were the positive associations between the A allele of rs36020 and attention problems on the CBCL and stereotypical behaviours on the ABC and between the C allele of rs1814270 and the number of trials required to complete the first WCST category. However, these associations did not remain after correction for multiple testing. The study results of this study do not support the association between the SLC6A2 and the diagnosis or phenotype of ASD. However, the study must be replicated in larger populations and with using more genetic markers.

Serotonin (5-HT) dysfunction has been involved in both movement and behavioral disorders. Serotonin pharmacology improves dyskinetic movements as well as depressive, anxious, aggressive and anorexic symptoms. Animal models have been useful to investigate more precisely to what extent 5-HT is involved and whether drugs targeting the 5-HT system can counteract the symptoms exhibited. We review existing rodent and non-human primate (NHP) animal models in which selective 5-HT or dual 5-HT-norepinephrine (NE) transporter inhibitors, as well as specific 5-HT receptors agonists and antagonists, monoamine oxidase A inhibitors (IMAO-A) and MDMA (Ecstasy) have been used. We review overlaps between the various drug classes involved. We confront behavioral paradigms and treatment regimen. Some but not all animal models and associated pharmacological treatments have been extensively studied in the litterature. In particular, the impact of selective serotonin reuptake inhibitors (SSRI) has been extensively investigated using a variety of pharmacological or genetic rodent models of depression, anxiety, aggressiveness. But the validity of these rodent models is questioned. On the contrary, few studies did address the potential impact of targeting the 5-HT system on NHP models of behavioral disorders, despite the fact that those models may match more closely to human pathologies. Further investigations with carefull behavioral analysis will improve our understanding of neural bases underlying the pathophysiology of movement and behavioral disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (>3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD), we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.

Background: The partial trisomy 9q syndrome is a well-defined chromosomal disorder with over 40 reported cases in the literature. However, 9q duplications derived from an insertional translocation have rarely been reported., Methods: Cytogenetic and molecular analyses using G-banding, fluorescence in situ hybridization, and single nucleotide polymorphism array were performed in a 25-year-old male patient with intellectual disability, behavioral abnormalities, speech delay, postnatal growth retardation, distinctive facial features, and pyloric stenosis., Results: G-banding analysis showed an extra chromosome segment of unknown origin inserted into band 4q25. A 16,747,601 bp duplication of 9q21.32q31.1 inserted into band 4q25 and a balanced (4;9) insertional translocation were identified by single nucleotide polymorphism array and fluorescence in situ hybridization analysis respectively in the patient and his healthy father. A literature review was performed to refine genotype-phenotype correlation of the partial trisomy 9q syndrome., Conclusion: This is the first report on the molecular characterization of a partial trisomy 9q syndrome derived from an insertional translocation between nonhomologous chromosomes. Our findings provide important information for genetic counseling and prenatal diagnosis of future pregnancies in this family., (Copyright © 2014 Wiley Periodicals, Inc.)

The Quebec Longitudinal Study of Kindergarten Children (QLSKC) is an ongoing population-based prospective longitudinal study presently spanning ages 6-29 years, designed to study the prevalence, risk factors, development and consequences of behavioural and emotional problems during elementary school. Kindergarten boys and girls attending French-speaking public schools in the Canadian province of Quebec during the 1986-87 and 1987-88 school years were included in the cohort: 2000 children representative of the population and 1017 children exhibiting disruptive behaviour problems. To date, 12 waves of data have been collected, and three generations of participants have been involved in the study (i.e. the study child, his parents and the first child of the study child). Information on demographics, psycho-social and lifestyle factors, child and family member characteristics (physical and mental health), and outcomes such as psychiatric diagnoses, delinquency or school diploma were assessed during three important developmental stages (childhood, adolescence and early adulthood). Blood samples were also collected in early adulthood for genetic analyses. Information on publications, available data and access to data can be found on the following website (http://www.gripinfo.ca/Grip/Public/www/).

Background: Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome., Method: Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems., Results: One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively., Conclusion: One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems., (© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.)

The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory.

Aims: In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interindividual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TDO2 gene that could affect expression and/or activity of TDO through glucocorticoid induction., Methods: Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines., Results: We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions., Conclusions: Correlational studies in larger samples could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interindividual variability observed in behavioural responses to acute ethanol consumption.

Background: Intellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 - 1% in individuals with ID) associated with EEG and behavioral problems., Methods: We assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners' Rating Scales Revised (CRS-R:L)., Results: All individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported., Conclusion: Our observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers.

THY-Tau22 mice constitute an animal model for tau aggregation, a hallmark in Alzheimer's disease (AD) and Tauopathies. Our previous studies have shown learning and memory deficits and changes in synaptic plasticity in the hippocampus in THY-Tau22 mice that are consistent with the learning impairments seen in AD-patients. However, behavioral disturbances are the most important problems in the management of AD and are major determinants of nursing home placement. Thus, we hypothesized that THY-Tau22 mice would demonstrate, in addition to the cognitive impairments, at least some behavioral and psychological signs and symptoms of dementia (BPSD). We found that 12 months old THY-Tau22 mice, relative to wild-type (WT) littermates display increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Moreover, these changes were linked to a decreased hippocampal concentration in serotonin, or 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects and alleviate BPSD in the human disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The retinaldehyde dehydrogenase 3 (Raldh3) gene encodes a major retinoic acid synthesizing enzyme and is highly expressed in the inner ear during embryogenesis. We found that mice deficient in Raldh3 bear severe impairment in vestibular functions. These mutant mice exhibited spontaneous circling/tilted behaviors and performed poorly in several vestibular-motor function tests. In addition, video-oculography revealed a complete loss of the maculo-ocular reflex and a significant reduction in the horizontal angular vestibulo-ocular reflex, indicating that detection of both linear acceleration and angular rotation were compromised in the mutants. Consistent with these behavioral and functional deficiencies, morphological anomalies, characterized by a smaller vestibular organ with thinner semicircular canals and a significant reduction in the number of otoconia in the saccule and the utricle, were consistently observed in the Raldh3 mutants. The loss of otoconia in the mutants may be attributed, at least in part, to significantly reduced expression of Otop1, which encodes a protein known to be involved in calcium regulation in the otolithic organs. Our data thus reveal a previously unrecognized role of Raldh3 in structural and functional development of the vestibular end organs.

Married adults show better psychological adjustment and physical health than their separated/divorced or never-married counterparts. However, this apparent "marriage benefit" may be due to social selection, social causation, or both processes. Genetically informed research designs offer critical advantages for helping to disentangle selection from causation by controlling for measured and unmeasured genetic and shared environmental selection. Using young-adult twin and sibling pairs from the National Longitudinal Study of Adolescent Health (Harris, 2009), we conducted genetically informed analyses of the association between entry into marriage, cohabitation, or singlehood and multiple indices of psychological and physical health. The relation between physical health and marriage was completely explained by nonrandom selection. For internalizing behaviors, selection did not fully explain the benefits of marriage or cohabitation relative to being single, whereas for externalizing symptoms, marriage predicted benefits over cohabitation. The genetically informed approach provides perhaps the strongest nonexperimental evidence that these observed effects are causal., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson's disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions.