Association of Pre- and Perinatal Risk Factors With Tourette Syndrome or Chronic Tic Disorders in a Korean School-Age Population.

Objectives: Tic disorders are highly heritable; however, growing evidence suggests that environmental factors play a significant role in their pathogenesis. Studies on these factors have been inconsistent, with conflicting results. Therefore, this study aimed to examine the associations of pre- and perinatal exposure to Tourette syndrome (TS) or chronic tic disorders (CTD) in Korean school-aged children. Methods: This case-control study used data from a large prospective cohort study. The primary outcome was TS/CTD diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version-Korean Version. Demographic, pre-, and perinatal information was obtained from the maternal questionnaires. Data between the TS/CTD and control groups were compared using the chi-squared or Student's t-test, as appropriate. Two-step logistic regression analyses were used to test the association between TS/CTD and pre- and perinatal risk factors. Results: We included of 223 children (78 with TS/CTD and 145 controls). Significant differences in the demographic data between the two groups were observed. The male sex ratio, mean parental age, parental final education level, and family history of tics were included as confounders. In the final adjusted multivariable model, TS/CTD was significantly associated with antiemetic exposure during pregnancy (odds ratio [OR]=16.61, 95% confidence interval [CI] 1.49-185.22, p=0.02) and medically assisted reproduction (OR=7.89, 95% CI 2.28-27.28, p=0.01). Conclusion: Antiemetic exposure and medically assisted reproduction are significantly associated with the risk of TS/CTD. These results should be replicated in future prospective and gene-by-environment studies.

Erratum: A Study of the Reliability and Validity of the Korean Version of DSM-5 Symptom Measure-Inattention and Anger for Parent and Guardian of Child Age 6 to 17.

[This corrects the article on p. 71 in vol. 32, PMID: 33828406.].

Psychological Aspects of Child Maltreatment.

In this review, we provide information about the etiology, risk factors, and clinical presentations of maltreatment to help clinicians better understand child abuse and neglect. Child maltreatment is a major global health challenge that can result in severe consequences. Abused and neglected children are likely to develop psychiatric disorders, such as major depressive disorder, anxiety disorder, and posttraumatic stress disorder. Understanding child maltreatment is expected to prevent and reduce victimization in children, adolescents, and their families.

Alterations in Social Brain Network Topology at Rest in Children With Autism Spectrum Disorder.

OBJECTIVE: Underconnectivity in the resting brain is not consistent in autism spectrum disorder (ASD). However, it is known that the functional connectivity of the default mode network is mainly decreased in childhood ASD. This study investigated the brain network topology as the changes in the connection strength and network efficiency in childhood ASD, including the early developmental stages. METHODS: In this study, 31 ASD children aged 2-11 years were compared with 31 age and sex-matched children showing typical development. We explored the functional connectivity based on graph filtration by assessing the single linkage distance and global and nodal efficiencies using resting-state functional magnetic resonance imaging. The relationship between functional connectivity and clinical scores was also analyzed. RESULTS: Underconnectivities within the posterior default mode network subregions and between the inferior parietal lobule and inferior frontal/superior temporal regions were observed in the ASD group. These areas significantly correlated with the clinical phenotypes. The global, local, and nodal network efficiencies were lower in children with ASD than in those with typical development. In the preschool-age children (2-6 years) with ASD, the anterior-posterior connectivity of the default mode network and cerebellar connectivity were reduced. CONCLUSION: The observed topological reorganization, underconnectivity, and disrupted efficiency in the default mode network subregions and social function-related regions could be significant biomarkers of childhood ASD.

Prenatal and postnatal exposures to four metals mixture and IQ in 6-year-old children: A prospective cohort study in South Korea.

BACKGROUND: Humans are exposed to a mixture of metals during their lifetime; however, evidence of neurotoxicity of such mixtures in critical time windows is still insufficient. We aimed to elucidate the associations of four metals mixture across multiple time points with children's intelligence quotient (IQ) in a prospective cohort study. METHODS: Prenatal exposure and exposure at age 4 and 6 years to four types of blood metals, namely lead, mercury, cadmium, and manganese were quantified in 502 pregnant women and their children who participated in the Environment and Development Cohort study. Children' s IQ scores were assessed using the Wechsler Intelligence Scale at age 6. Bayesian kernel machine regression (BKMR), quantile g-computation models, and elastic net (ENET) models were used to assess the associations of their blood metals mixture with IQ scores. RESULTS: Multivariate linear regression models indicated that postnatal blood manganese exposure at the age of 4 years was significantly negatively associated with children's IQ [ß =  - 5.99, 95% confidence interval (CI): -11.37 to - 0.61]. In the multi-chemical BKMR and quantile g-computation model, statistically significant inverse associations were found between the mixture of prenatal and postnatal metals and children's IQ score (Difference in children' IQ per quartile increase: -2.83; 95% CI: -5.28, -0.38). Interestingly, we found that manganese levels at both age of 4 and 6 years were contributing factors to children's IQ in the mixture models, namely, BKMR, quantile g-computation, and ENET models. CONCLUSIONS: Multi-pollutant mixtures of prenatal and postnatal exposures to four metals affected child IQ at 6 years of age. We found a relationship between manganese exposure at both age 4, and 6 years and children's IQ. Additional studies are warranted to confirm these associations and to control the exposure to different metals during pregnancy and preschool childhood.

A Study of the Reliability and Validity of the Korean Version of DSM-5 Symptom Measure-Inattention and Anger for Parent and Guardian of Child Age 6 to 17.

OBJECTIVES: This study was conducted to investigate the reliability and validity of the Korean version of the DSM-5 Level 2 Cross-Cutting Symptom Measure-inattention [Swanson, Nolan and Pelham, version IV (SNAP-IV)] and anger [Patient-Reported Outcome Measurement Information System (PROMIS) Anger] for parents and guardians of children aged 6-17 years. METHODS: We included 104 children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD), ADHD with anxiety and depression, depressive disorder, anxiety disorder, and tic disorder with somatic symptoms (ADHD=41, depression=9, anxiety=14, ADHD+anxious depression=11, tic+somatic symptoms=29). Their ages ranged from 8 years to 15 years. The participants' mothers completed the SNAP-IV, PROMIS Anger scale, Korean version of the IOWA Conners Rating Scale (K-IOWA), and Korean ADHD Rating Scale (K-ARS) so that the reliability and validity of the SNAP-IV and PROMIS Anger scales, which are DSM-5 scales for assessing inattention and anger of children and adolescents, could be examined. RESULTS: The reliability coefficient of SNAP-IV (Cronbach's α) was 0.94. The correlation coefficients between SNAP-IV, K-IOWA inattention, and K-ARS inattention scores ranged from 0.73 to 0.86. The mean SNAP-IV scores of the ADHD and the ADHD+anxious depression groups were significantly higher than those of the anxiety and the tic+somatic symptoms groups. The reliability coefficient of the PROMIS Anger was 0.91. The correlation coefficient between PROMIS Anger and K-IOWA oppositional/defiant scores was 0.75. The PROMIS Anger mean score of the ADHD+anxious depression group tended to be higher than that of the other groups. CONCLUSION: These results suggest that the Korean version of the DSM-5 Level 2 Cross-Cutting Symptom Measure-inattention and anger for parent and guardian of child age 6-17 might be a reliable and valid test and may be useful for screening children and adolescents with ADHD.

Normative Data for the Logical Memory Subtest of the Wechsler Memory Scale-IV in Middle-Aged and Elderly Korean People.

OBJECTIVE: The purpose of this study is to identify the demographic variables that are affecting performances on the Logical Memory (LM) subtest included in the Korean version of the Wechsler Memory Scale (WMS)-IV and to provide normative data on the LM subtest for the middle-age and elderly Korean people. METHODS: The participants were 435 non-demented adults aging from 50 to 90 and with the educational level ranging from 0 to 21 years. RESULTS: Age and education were found to be significantly associated with performance on the LM subtest, while gender effect was not statistically significant. Therefore, we stratified the norm blocks by age and education. Age was divided into three groups: 50-59, 60-74, and 75-90 years. Education was stratified into three groups: 0-8 years, 9-12 years, and 13 years or more. CONCLUSION: The normative data provided in the current study are expected to be useful in clinical and research settings to detect or define subtle changes in episodic memory in Korean adults and elderly, and can also be used for cross-cultural comparison of verbal episodic memory performance among elderly populations using different languages.

Psychiatric Manifestation in Patients with Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although its major manifestation is motor symptoms, resulting from the loss of dopaminergic neurons in the substantia nigra, psychiatric symptoms, such as depression, anxiety, hallucination, delusion, apathy and anhedonia, impulsive and compulsive behaviors, and cognitive dysfunction, may also manifest in most patients with PD. Given that the quality of life - and the need for institutionalization - is so highly dependent on the psychiatric well-being of patients with PD, psychiatric symptoms are of high clinical significance. We reviewed the prevalence, risk factors, pathophysiology, and treatment of psychiatric symptoms to get a better understanding of PD for improved management.

TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.

UNLABELLED: Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. SIGNIFICANCE: In recent years, "pathway dependence" has been revealed in specific types of human cancer, which can be important because they pinpoint proteins that are particularly vulnerable to antitumor-targeted inhibition (so-called Achilles' heel proteins). Here, we use RNAi technology to identify a novel oncogenic pathway that involves aberrant activation of the TYK2 tyrosine kinase and its downstream substrate, STAT1, which ultimately promotes T-ALL cell survival through the upregulation of BCL2 expression

Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia.

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.

Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia.

To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.

Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression.

A growing body of evidence indicates that early mitotic inhibitor 1 (Emi1) is essential for genomic stability, but how this function relates to embryonic development and cancer pathogenesis remains unclear. We have identified a zebrafish mutant line in which deficient emi1 gene expression results in multilineage hematopoietic defects and widespread developmental defects that are p53 independent. Cell cycle analyses of Emi1-depleted zebrafish or human cells showed chromosomal rereplication, and metaphase preparations from mutant zebrafish embryos revealed rereplicated, unsegregated chromosomes and polyploidy. Furthermore, EMI1-depleted mammalian cells relied on topoisomerase II alpha-dependent mitotic decatenation to progress through metaphase. Interestingly, the loss of a single emi1 allele in the absence of p53 enhanced the susceptibility of adult fish to neural sheath tumorigenesis. Our results cast Emi1 as a critical regulator of genomic fidelity during embryogenesis and suggest that the factor may act as a tumor suppressor.

High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia.

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.

Activating mutations in ALK provide a therapeutic target in neuroblastoma.

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.