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Abstract: Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

The aims of our study are: i) to explore whether plasma levels of BDNF/GDNF are valuable in the diagnosis of first-episode depression; ii) to discuss whether there is an association between peripheral plasma levels of BDNF/GDNF and patients' depression severity and cognitive dysfunction; iii) to explore the association between plasma levels of BDNF/GDNF and the effectiveness of antidepressant treatment.Ninety patients with first-episode unmedicated MDD and healthy controls were recruited. MDD patients were treated with antidepressant medication for 8 weeks. Patients were assessed for clinical symptoms using HDRS-17 and HAMA-14. Social and neurocognitive functioning of all subjects was assessed at baseline using the Functional Assessment Test Short Form (FAST) and the MATRICS Consensus Cognitive Battery (MCCB). At the same time, peripheral venous blood was drawn from all subjects for BDNF/GDNF peripheral plasma level analysis at baseline and after 8 weeks of treatment.The baseline BDNF/GDNF levels in MDD patients were significantly lower than that in healthy controls. The area under ROC curve (AUC) of baseline plasma BDNF and GDNF levels predicting MDD was 0.776 (95 % CI: 0.705-0.846, p 0.001) and 0.864 (95 % CI: 0.808-0.920, p 0.001), respectively. The baseline GDNF level (beta = 0.425, p = 0.001), the autonomy score of FAST (beta = -0.247, p = 0.037) and BACS-SC score of MCCB (beta = 0.323, p = 0.039) were predictors of HDRS-17 reduction rate after 8 weeks' antidepressant treatment.A longer follow-up period than 8 weeks may make the results more convincing, and the sample size of this study is still insufficient.The decreased plasma levels of BDNF and GDNF are strong indicators for predicting the occurrence of MDD. This preliminary finding highlighted the value of GDNF plasma concentrations in the diagnosis of MDD and the prognosis of antidepressant treatment.

A line of evidence has shown that childhood trauma and patterns of H-shaped sulci in the orbitofrontal cortex (OFC) are associated with cognitive deficits in patients with schizophrenia. Studies have also suggested that childhood trauma is associated with OFC volumetrics. This study investigated the interrelationship between childhood trauma, OFC H-shaped sulci volume and cognitive function in patients with first-episode schizophrenia. We hypothesized that OFC H-shaped sulci volume would mediate the relationship between childhood trauma and cognitive function in patients with first-episode schizophrenia.We recruited patients with first-episode schizophrenia (Patients with first-episode schizophrenia had smaller left OFC H-shaped sulci volumes, more severe childhood trauma experiences and worse cognitive function than healthy controls. CTQ total score and emotional and physical neglect subscores were negatively correlated with left OFC H-shaped sulci volume. CTQ total score and emotional neglect and sexual abuse subscores were negatively correlated with cognitive function in patients with first-episode schizophrenia. Interestingly, the CTQ total score and physical neglect subscore were positively correlated with cognitive function in healthy controls. Left OFC H-shaped sulci volume played a mediating role in CTQ emotional neglect subscore, CTQ total score and MCCB composite score.The small sample size and retrospective design need to be considered.Childhood trauma might contribute to cognitive deficits in patients with first-episode schizophrenia by affecting left OFC H-shaped sulci volume. This finding can help in the design of strategies to improve cognitive function in patients with first-episode schizophrenia.

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10–5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q f KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10–12 ≤ p ≤ 0.050; q –4 ≤ p ≤ 0.008; q –3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10–3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10–19 ≤ p ≤ 0.050; q –19 ≤ p ≤ 1.0 × 10–4; q KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

Background Alcohol dependence (AD) is a disorder with a high recurrence rate that leads to a considerable public health burden. The risk of relapse appears to be related to a complex interplay of multiple factors. Herein, we aimed to explore the potential neural predictors of relapse in Chinese male patients with AD. Methods This study enrolled 58 male patients with AD who had undergone acute detoxification. General demographic information and clinical features were collected. Magnetic resonance imaging (MRI) data were used to measure cortical thickness across 34 regions of the brain. Patients were followed up at 6 months, and 51 patients completed the follow-up visit. These patients were divided into a relapser and an abstainer group. A binary logistic regression analysis was performed to investigate the potential risk factors of relapse. Results Compared to abstainers, relapsers showed higher inattention and non-planning impulsivity on the 11th version of the Barratt Impulsive Scale. The cortical thicknesses of the inferior-parietal lobule were significantly greater in abstainers compared with those in relapsers. Furthermore, binary logistic regression analysis showed that the thickness of the inferior parietal lobule predicted relapse. Conclusions Relapsers show poorer impulse control than abstainers, and MRI imaging shows a decreased thickness of the inferior parietal lobule in relapsers. Our results indicate the thickness of the inferior parietal lobule as a potential relapse predictor in male patients with AD.

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10–5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10–22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Accumulating evidence suggests that hypothalamic-pituitary-adrenal axis dysfunction might play an important role in the pathophysiology of schizophrenia. The aim of this study was to explore the cortisol response to psychological stress in patients with schizophrenia. In this study, patients with schizophrenia (n = 104) and healthy volunteers (n = 59) were asked to complete psychological stress challenge tasks, which included the Paced Auditory Serial Addition Task and Mirror-Tracing Persistence Task, and pre- and post-task saliva samples were collected to measure cortisol levels. Emotions and psychopathology were assessed by the Positive and Negative Affect Schedule and Positive and Negative Syndrome Scale. The results showed (1) that the cortisol response and negative emotions in patients with schizophrenia differed significantly from those in healthy volunteers, (2) there were significant interactions between the sampling time and diagnosis for saliva cortisol levels, (3) there were significant interactions between the scoring time and diagnosis for the negative affect score of the PANAS, and (4) the changes in salivary cortisol levels and negative affect scores before and after the psychological stress challenge tasks were not correlated with clinical symptoms in patients with schizophrenia. These findings indicated an abnormal cortisol profile in patients with schizophrenia, which might be a biological characteristic of the disease.

ObjectiveOur study aimed to investigate the associations between the serum level of kynurenine pathway (KP) metabolites and P50 auditory gating in non-smoking patients with first-episode schizophrenia (FES).Materials and methodsIn this study, 82 non-smoking patients with FES and 73 healthy controls (HC). P50 auditory gating was measured using a fully functional digital 64-channel EEG system, and the components included S1 amplitude, S2 amplitude, gating ratio (S2/S1), and amplitude difference (S1–S2). Serum levels of kynurenine and kynurenine acid were assessed using a combination of liquid chromatography with tandem mass spectrometry. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS).ResultsThe serum kynurenine (251.46 ± 65.93 ng/ml vs. 320.65 ± 65.89 ng/ml, t = –6.38, p < 0.001), and kynurenine acid levels (5.19 ± 2.22 ng/ml vs. 13.26 ± 4.23 ng/ml, t = –14.73, p < 0.001), S1 amplitude [2.88 (1.79, 3.78) μV vs. 3.08 (2.46, 4.56) μV, Z = –2.17, p = 0.030] and S1–S2 [1.60 (0.63, 2.49) μV vs. 1.92 (1.12, 2.93) μV, Z = –2.23, p = 0.026] in patients with FES were significantly lower than those in HC. The serum kynurenine and kynurenine acid levels were negatively associated with S1–S2 (r = –0.32, p = 0.004 and r = –0.42, p < 0.001; respectively) and positively correlated with S2/S1 ratio (r = 0.34, p = 0.002 and r = 0.35, p = 0.002; respectively) in patients.ConclusionOur findings suggested that neuroactive metabolites of the KP might play an important role in sensory gating deficit in first episode patients with schizophrenia. Furthermore, metabolites of the KP may be a new target for the treatment of cognitive impairments in schizophrenia.

Alzheimer's disease (AD) is a chronic, progressive, degenerative disease characterized by cognitive dysfunction, including verbal memory loss. Studies were lacking in examining the longitudinal effect of polygenic hazard score on the Rey Auditory Verbal Learning Test-Delayed Total (AVDELTOT) score (a common measure of verbal memory). A key step in analyzing longitudinal changes in cognitive measures using a linear mixed model (LMM) is choosing a suitable covariance structure.The study aims to determine the association between the polygenic hazard score and the AVDELTOT score accounting for repeated measures (the covariance structure).The AVDELTOT scores were collected at baseline, 12 months, 24 months, 36 months, and 48 months from 283 participants with AD, 347 with cognitive normal, and 846 with mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative. The Bayesian information criterion statistic was used to select the best covariance structure from 10 covariance structures in longitudinal analysis of AVDELTOT scores. The multivariable LMM was used to investigate the effect of polygenic hazard score status (low vs. medium vs. high) on changes in AVDELTOT scores while adjusted for age, gender, education, APOE-ε4 genotype, and baseline Mini-Mental State Examination score.One-way analysis of variance revealed significant differences in AVDELTOT scores, Mini-Mental State Examination scores, and polygenic hazard scores among AD diagnoses at baseline. Bayesian information criterion favored the compound symmetry covariance structure in the LMM analysis. Using the multivariate LMM, the APOE-ε4 allele and high polygenic hazard score value was significantly associated with AVDELTOT declines. Significant polygenic hazard score status by follow-up visit interactions was discovered.Our findings provide the first evidence of the effect of polygenic hazard score status and APOE-ε4 allele on declines in verbal memory in people with AD.

Several studies have reported compromised white matter integrity, and that some inflammatory mediators may underlie this functional dysconnectivity in brain of patients with schizophrenia. The immune-inflammatory response system and compensatory immune-regulatory reflex system (IRS/CIRS) are novel biomarkers for exploring the role of immune imbalance in the pathophysiological mechanism of schizophrenia. This study aimed to explore the little-known area regarding the composite score of peripheral cytokines, the IRS/CIRS, and its correlation with white matter integrity and the specific microstructures most affected in schizophrenia. First-episode patients with schizophrenia (FEPS, n = 94) and age- and sex-matched healthy controls (HCs, n = 50) were enrolled in this study. Plasma cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA), and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). The whole brain white matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging (DTI) using a 3-T Prisma MRI scanner. The IRS/CIRS in FEPS was significantly higher than that in HCs (p = 1.5×10− 5) and Cohen’s d effect size was d = 0.74. FEPS had a significantly lower whole-brain white matter average FA (p = 0.032), which was negatively associated with IRS/CIRS (p = 0.029, adjusting for age, gender, years of education, BMI, and total intracranial volume), but not in the HCs (p > 0.05). Among the white matter microstructures, only the cortico-spinal tract was significantly correlated with IRS/CIRS in FEPS (r=-0.543, p = 0.0009). Therefore, elevated IRS/CIRS may affect the white matter in FEPS.

ObjectivePrevious studies have implicated intricate interactions between innate immunity and the brain in schizophrenia. Monocytic Toll-like receptor (TLR) 4 signaling, a crucial “sensor” of innate immunity, was reported to be over-activated in link with cognitive impairment in schizophrenia. As TLR4 is predominantly expressed on gliocytes prior to expression in neurons, we hypothesized that higher TLR4 levels may contribute to cognitive deterioration by affecting white matter microstructure.MethodsForty-four patients with stable chronic schizophrenia (SCS) and 59 healthy controls (HCs) were recruited in this study. The monocytic function was detected with lipopolysaccharide (LPS) stimulation to simulate bacterial infection. Basal and LPS- stimulated levels of TLR4, nuclear factor-kappa B (NF-κB), and interleukin (IL)-1β were quantified with flow cytometry. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB) and psychopathological symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). We employed diffusion tensor imaging with a 3-T scanner and evaluated white-matter integrity with fractional anisotropy (FA). Subcortical volume and cortical thickness were also assessed.ResultsThe TLR4/NF-κB/IL-1β signaling pathway was activated in patients with SCS, but responded sluggishly to LPS stimulation when compared with HCs. Furthermore, monocytic TLR4 expressions were inversely correlated with cognitive function and white matter FA, but not with cortical thickness or subcortical gray matter volume in schizophrenia.ConclusionOur findings support altered TLR4 signaling pathway activity in association with deficits in cognition and white matter integrity in schizophrenia.

Previous genome-wide association studies (GWAS) reported that the allele C of rs945270 of the kinectin 1 gene (KTN1) most significantly increased the gray matter volume (GMV) of the putamen and modestly regulated the risk for attention deficit hyperactivity disorder (ADHD). On the other hand, ADHD is known to be associated with a reduction in subcortical and cortical GMVs. Here, we examined the interrelationships of the GMVs, rs945270 alleles, and ADHD symptom scores in the same cohort of children. With data of rs945270 genotypes, GMVs of 118 brain regions, and ADHD symptom scores of 3372 boys and 3129 girls of the Adolescent Brain Cognition Development project, we employed linear regression analyses to examine the pairwise correlations adjusted for the third of the three traits and other relevant covariates, and examine their mediation effects. We found that the major allele C of rs945270 modestly increased risk for ADHD in males only when controlling for the confounding effects of the GMV of any one of the 118 cerebral regions (0.026 ≤ p ≤ 0.059: Top two: left and right putamen). This allele also significantly increased putamen GMV in males alone (left p = 2.8 × 10−5, and right p = 9.4 × 10−5; α = 2.1 × 10−4) and modestly increased other subcortical and cortical GMVs in both sexes (α p −7 ≤ p α; Top two: left pallidum and putamen) and males (3.5 × 10−6 ≤ p α), respectively. Finally, the left and right putamen GMVs reduced 14.0% and 11.7% of the risk effects of allele C on ADHD, and allele C strengthened 4.5% (left) and 12.2% (right) of the protective effects of putamen GMVs on ADHD risk, respectively. We concluded that the rs945270-GMVs-ADHD relationships were sex-different. In males, the major allele C of rs945270 increased risk for ADHD, which was compromised by putamen GMVs; this allele also but only significantly increased putamen GMVs that then significantly protected against ADHD risk. In females, the top two GMVs significantly decreasing ADHD risk were left pallidum and putamen GMVs. Basal ganglia the left putamen in particular play the most critical role in the pathogenesis of ADHD.

Objectives: Genome-wide association studies have identified a significant risk gene, CACNA1C, for schizophrenia. In this study, we comprehensively investigated a large set of CACNA1C single-nucleotide polymorphisms (SNPs) to identify the replicable risk alleles for schizophrenia and explore their biological functions. Methods: One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism–schizophrenia associations. The regulatory effects of risk alleles on CACNA1C messenger RNA expression were examined. The most robust risk tagSNP (rs1006737) was meta-analyzed on 17 studies (74,122 cases vs 109,062 controls), and associated with the gray matter volumes of seven subcortical structures in 38,258 Europeans, and the surface areas and thickness of 34 cortical regions in 33,992 Europeans and 2944 non-Europeans. Results: Forty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10−4 ⩽ p ⩽ 0.049). This variant block was consistently associated with schizophrenia across four independent Psychiatric Genomics Consortium cohorts (79,645 cases vs 109,590 controls; 2.5 × 10–17 ⩽ p ⩽ 0.017). This block showed significant expression quantitative trait loci in three independent European brain cohorts (5.1 × 10–12 ⩽ p ⩽ 8.3 × 10–3) and could be tagged by the most significant risk single-nucleotide polymorphism rs1006737. The minor allele A of rs1006737 significantly increased risk for schizophrenia across the Jewish and European samples ( p = 0.029 and 0.004, respectively), and this association was highly significant in the meta-analysis ( p = 1.62 × 10–42). This allele also significantly altered the CACNA1C messenger RNA expression in five brain regions (5.1 × 10–12 ⩽ p ⩽ 0.05), decreased the gray matter volume of thalamus ( p = 0.010), the surface area of isthmus cingulate cortex ( p = 0.013) and the thickness of transverse temporal and superior temporal sulcus cortexes (0.005 ⩽ p ⩽ 0.043). Conclusion: We identified an independent, replicable, functional, and significant risk variant block at CACNA1C for schizophrenia, which could be tagged by the most robust risk marker rs1006737, suggesting an important role of CACNA1C in the pathogenesis of schizophrenia.

Background Accumulating evidence has converged to suggest that childhood trauma may contribute to bipolar disorder (BD). This study aimed to investigate the patterns of childhood trauma among patients with bipolar I (BD-I) and bipolar II (BD-II) disorders, according to DSM-IV and in contrast with healthy volunteers. We also explored whether the relationship between childhood trauma and onset of bipolar disorder is mediated by immature defense mechanisms. Methods Participants were patients with BD-I (n=44) and BD-II (n = 42), and healthy controls (HCs, n = 43). Childhood traumatic experiences and defense mechanisms were assessed by the Childhood Trauma Questionnaire (CTQ) and the Defense Style Questionnaire (DSQ), respectively. Results BD patients experienced more severe childhood trauma than HCs. Physical neglect sub-score and total score of the CTQ had both direct and indirect effects on the diagnosis of BD-I, and an immature defense style mediated the indirect effects. The diagnosis of BD-II was mainly related to the physical neglect and emotional abuse subs-core and total score of the CTQ, as mediated by the immature defense mechanisms. BD-I and BD-II significantly differed in the emotional abuse sub-score of the CTQ. Conclusions Physical neglect sub-score and total score of the CTQ were associated with the diagnosis of BD (both BD-I and BD-II), as mediated by an immature defense style. Furthermore, emotional abuse might be an important risk factor for BD-II compared to BD-I. These findings may inform risk reduction and psychosocial intervention strategies to prevent and treat patients with bipolar disorders.

The mechanism by which high homocysteine (HCY) may aggravate cognitive impairment in patients with schizophrenia is not well understood. We aimed to test the hypothesis that hyperhomocysteinaemia may exacerbate cognitive deficits by mediating the decrease in cortical thickness in patients with schizophrenia. One hundred and sixty-seven first-episode patients with schizophrenia (FEPS) and 120 healthy controls (HCs) were included. Psychopathology and cognitive function were assessed using the Positive and Negative Symptom Scale and Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), respectively. Brain cortical thickness was measured by 3.0 T high-resolution magnetic resonance imaging. Serum HCY levels were tested using a sandwich enzyme-linked immunosorbent assay. Our findings showed that HCY levels in the FEPS were significantly higher than those in the HCs (P 0.001). The MCCB total and subtest scores in the patients were significantly lower than those in the HCs (P 0.001). The HCs had significantly higher cortical thickness than the patients (P 0.001). Serum HCY levels were negatively correlated with Working Memory, Attention/Vigilance, and MCCB total scores in the FEPS (P 0.05). Brain cortical thickness had positive moderating effects on cognitive impairment in FEPS with high HCY after controlling for sex, age, and education (P 0.05). In HCs with high HCY, brain cortical thickness had no mediating or moderating effects on cognitive impairment. Compared with HCs, FEPS had thinner grey matter thickness, furthermore, the grey matter thickness might play a crucial role in relationship between high HCY and cognitive deficits.

Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p

Background: Increasing facts demonstrated the occurrence of sensory gating defects in schizophrenic sufferers, which had relation to the weakening of P50 response inhibition and had association with α7 nicotinic acetylcholine receptor (α7nAChR). Nevertheless, as a noncompetitive antagonist of α7nAChR, Kynurenic acid (KYNA) cannot cross the blood-brain barrier (BBB). In contrast, Kynurenine (KYN), as a precursor of KYNA metabolism, is capable of crossing the BBB. The exploration focused on investigatating the relation of the serum KYN level with P50 among first-episode patients with schizophrenia (FEPS).Methods: In the exploration, measurement of P50 sensory gating was conducted among 82 FEPS and 73 healthy controls (HC). Positive and Negative Syndrome Scale (PANSS) was used for assessing the psychopathology; and liquid chromatography-tandem mass spectrometry was utilized for measuring the the serum KYN level. Spearman rank correlation coefficient was used to test the correlation between P50 index and serum KYN level and PANSS score. Pearson correlation coefficient was used to test the correlation between serum KYN level and PANSS score.Results: The serum KYN levels[(251.46 ± 65.93) ng/ml vs. (320.65 ± 65.89) ng/ml, t = -6.38, p < 0.001], S1 amplitude [ (2.88(1.79, 3.78) μV vs. 3.08(2.46, 4.56) μV , Z = -2.17, p =0.030] and S1 minus S2 amplitude [1.60(0.63, 2.49) μV vs. 1.92(1.12, 2.93) μV , Z = -2.23, p = 0.026] in FEPS were apparently lower than those in the HC. An obviously inverse correlation was seen between S1 minus S2 amplitude and the serum KYN levels (r = -0.32, p = 0.004) in the FEPS.

Accumulating evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction might play an important role in the pathophysiology of schizophrenia. This study aimed to explore the cortisol response to psychological stress in patients with schizophrenia. In this study, patients with schizophrenia (n = 104) and healthy volunteers (n = 59) were asked to complete psychological stress challenge tasks, which included the Paced Auditory Serial Addition Task and Mirror-Tracing Persistence Task, and then, saliva was collected to measure cortisol levels. Emotions and psychopathology were assessed by the Positive and Negative Affect Schedule (PANAS) and Positive and Negative Syndrome Scale (PANSS). The results showed (1) that the cortisol stress response and negative emotions in patients with schizophrenia differed significantly from those in healthy controls; (2) there were significant interactions between sampling time and diagnosis for saliva cortisol levels; (3) there were significant interactions between scoring time and diagnosis for the negative affect score of the PANAS; and (4) the changes in salivary cortisol levels and negative affect scores before and after the psychological stress challenge tasks were not correlated with clinical symptoms in patients with schizophrenia. These findings indicated that an abnormal cortisol stress response might be a stable biological characteristic of schizophrenia.

Studies have shown sensory gating deficits and severe childhood trauma in patients with schizophrenia; however, their relationship with this condition remains unclear. Here, we hypothesized that sensory gating deficits mediate the effects of childhood trauma on schizophrenia onset.We recruited 79 patients with first-episode schizophrenia (PFES) and 76 health controls (HC). The auditory conditioning (S1) and testing (S2) stimulus paradigm was used to detect P50 sensory gating. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma experiences.Compared with HC, the PFES group had more severe childhood trauma experiences together with sensory gating deficits. In a partial correlation analysis, sexual abuse was negatively correlated with the P50 S2 latency, physical neglect was negatively correlated with the S1 latency, while emotional neglect was positively correlated with the S2/S1 ratio and negatively correlated with the S1-S2 difference in the PFES group. However, there was no correlation between the CTQ total and each sub-scores and P50 indicators in the HC. The S1-S2 difference was the mediator between emotional neglect and the onset of schizophrenia.Childhood trauma might be associated with schizophrenia by influencing sensory gating deficits. Early intervention targeting childhood trauma might reduce the incidence of sensory gating deficits and thus schizophrenia.

Chinese one-child policy has been practiced for more than 30 years. With the policy that one couple can have two children being fully implemented from Jan 1, 2016 in China, the families with two or more children are increasing, and the family size, family structure and family relationship has been largely changed. Little is known about the difference in domestic violence (DV) among single- and multi-child families in China. This study compared the prevalence, causes, patterns, consequence of DV and the attitude towards DV among single-child and multi-child families in the same communities between ten years in China. Epidemiological surveys were conducted among single-child and multi-child families in the same communities during the period of 2001–2002 (group 2002) for 9451 families and 2011–2012 (group 2012) for 6859 families, respectively. The same investigation methods, questionnaires and investigators were used in the two surveys. The findings indicated that the child abuse has been increasing, and the child education being the issue has climbed to the top in multi-child families. The negative attitude towards DV stayed the same in both single- and multi-child families. It is suggested that the intervention strategies on DV should be adjusted to the new situations, especially with the arrival of more multi-child families in current China.

Background: Previous studies have implicated childhood trauma and abnormal brain-derived neurotrophic factor in the pathogenesis of schizophrenia. Here, we explored whether brain-derived neurotrophic factor levels mediated the relationship between childhood trauma and psychopathological symptoms in patients with first-episode schizophrenia. Methods: Patients with first-episode schizophrenia ( n = 192) and healthy controls ( n = 136) were enrolled. Childhood traumatic experiences and psychopathology were assessed by Childhood Trauma Questionnaire and Positive and Negative Syndrome Scale, respectively. Enzyme-linked immunosorbent assay was used to quantify brain-derived neurotrophic factor levels. Results: The patients with first-episode schizophrenia experienced more severe childhood trauma and had lower serum brain-derived neurotrophic factor levels than healthy controls. Emotional abuse and Childhood Trauma Questionnaire total score showed positive correlation with Positive and Negative Syndrome Scale positive, general psychopathological subscore and total score. Emotional neglect showed positive correlation with Positive and Negative Syndrome Scale positive subscore. Physical neglect was positively associated with Positive and Negative Syndrome Scale negative subscore. Emotional neglect and Childhood Trauma Questionnaire total score were negatively correlated with serum brain-derived neurotrophic factor levels. The serum brain-derived neurotrophic factor levels mediated the relationship between both Childhood Trauma Questionnaire total score and Positive and Negative Syndrome Scale total score and negative symptoms in the patients. The brain-derived neurotrophic factor levels also mediated the relationship between emotional neglect and Positive and Negative Syndrome Scale total score in the patients. Conclusion: Childhood trauma might contribute to the clinical symptoms of schizophrenia by affecting brain-derived neurotrophic factor levels. Perhaps we can prevent schizophrenia by reducing childhood traumatic experiences.

Background: Accumulating evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction might play an important role in the pathophysiology of schizophrenia. Cortisol secretion levels can reflect the function of the HPA axis.This study aimed to explore the cortisol response to psychological stress in patients with schizophrenia. Methods: In this cross-sectional study study, patients with schizophrenia (n = 104) and healthy volunteers (n = 59) were asked to complete psychological stress challenge tasks, which included the Paced Auditory Serial Addition Task and Mirror-Tracing Persistence Task, and then, saliva was collected to measure cortisol levels. Emotions and psychopathology were assessed by the Positive and Negative Affect Schedule (PANAS) and Positive and Negative Syndrome Scale (PANSS). Results: (1) that the cortisol stress response and negative emotions in patients with schizophrenia differed significantly from those in healthy controls; (2) there were significant interactions between sampling time and diagnosis for saliva cortisol levels; (3) there were significant interactions between scoring time and diagnosis for the negative affect score of the PANAS; and (4) the changes in salivary cortisol levels and negative affect scores before and after the psychological stress challenge tasks were not correlated with clinical symptoms in patients with schizophrenia. Conclusions: These findings indicated that an abnormal cortisol stress response might be a stable biological characteristic of schizophrenia.

Background: The study aimed to examine the antipsychotic treatment effect on the serum S100B and oxidative stress in patients with schizophrenia. Methods: Subjects consisted of patients with schizophrenia of first-episode drug-naive and drug-free acute phases, and met the DSM-IV diagnostic criteria for schizophrenia. All patients were treated with risperidone for eight weeks. Positive and Negative Syndrome Scale (PANSS) was evaluated, and serum levels of S100B and parameters of oxidative stress including total oxidative status (TOS) and malondialdehyde (MDA) were measured before and after antipsychotic treatment. A general linear random-effect model was used for data analysis. Results: Antipsychotic treatment with risperidone reduced the levels of S100B significantly in the first episode drug-naive patients with schizophrenia (Beta=24.89; p=0.0087) and marginally in the drug-free acute phase (Beta=15.65; p=0.093), no significant difference in the effect on S100B between patient groups (p=0.4785). In contrast, antipsychotic treatment increased the levels of MDA in drug-free acute phase schizophrenia (Beta=-6.55; p

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p10

Background The aim was to explore the associations between clinical symptoms, demographic variables, social and neurocognitive functioning in euthymic patients with bipolar disorder (BD) stratified by subgroups of DSM-IV BD (type I (BD-I) and type II (BD-II)) and occupational status (employed/unemployed), and to highlight the significance of occupational status when assessing social and neurocognitive functioning in euthymic BD patients. Methods A total of 81 euthymic BD patients were participated in the study. The severity of the depressive and manic/hypomanic symptoms was measured using the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Young Mania Rating Scale (YMRS), respectively. Social functioning and neurocognitive functioning were evaluated by the Functioning Assessment Short Test (FAST) and neurocognitive measures, respectively. Results Employed BD patients displayed greater social functioning (autonomy, occupational functioning, interpersonal relationship domain) and better verbal learning performance and speed of processing than unemployed BD patients. The correlation between neurocognitive functioning and social functioning was stronger in the employed group than in the unemployed group. There were no significant differences in neurocognitive and social functioning between the BD-I and BD-II groups, and the correlation between neurocognitive functioning and social functioning was similar between the BD-I and BD-II groups. Conclusion Employed BD patients may present greater occupational functioning and interpersonal relationships, as well as better verbal learning performance and speed of processing.

Genome-wide association studies have identified a significant risk gene,One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism-schizophrenia associations. The regulatory effects of risk alleles onForty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10We identified an independent, replicable, functional, and significant risk variant block at

Sleep disorders are one of the most common non-motor symptoms in Parkinson's disease (PD). It can cause a notable decrease in quality of life and functioning in PD patients, as well as place a huge burden on both patients and caregivers. The most cited sleep disorders in PD included insomnia, restless legs syndrome (RLS), rapid eye movement (REM), sleep behavior disorders (RBD), excessive daytime sleepiness (EDS) and sleep disordered breathing (SDB), which can appear alone or several at the same time. In this review, we listed the recommended pharmacological treatments for common sleep disorders in PD, and discussed the recommended dosages, benefits and side effects of relative drugs. We also discussed non-pharmacological treatments to improve sleep quality, including sleep hygiene education, exercise, deep brain stimulation, cognitive behavior therapy and complementary therapies. We tried to find proper interventions for different types of sleep disorders in PD, while minimizing relative side effects.

In the brain, AMPA receptors mediate fast excitatory neurotransmission, the dysfunction of which leads to neuropsychiatric disorders. Synaptic function of AMPA receptors is tightly controlled by a protein group called transmembrane AMPAR regulatory proteins (TARPs). TARP γ-8 (also known as CACNG8) preferentially expresses in the hippocampus, cortex and subcortical regions that are critical for emotion generation indicating its association with psychiatric disorders. Here, we identified rs10420324 (T/G), a SNP located in the human CACNG8 gene, regulated reporter gene expression in vitro and TARP γ-8 expression in the human brain. A guanine at the locus (rs10420324G) suppressed transcription likely through modulation of a local G-quadruplex DNA structure. Consistent with these observations, the frequency of rs10420324G was higher in patients with anti-social personality disorder (ASPD) than in controls, indicating that rs10420324G in CACNG8 is more voluntary for ASPD. We then characterized the behavior of TARP γ-8 knockout and heterozygous mice and found that consistent with ASPD patients who often exhibit impulsivity, aggression, risk taking, irresponsibility and callousness, a decreased γ-8 expression in mice displayed similar behaviors. Furthermore, we found that a decrease in TARP γ-8 expression impaired synaptic AMPAR functions in layer 2–3 pyramidal neurons of the prefrontal cortex, a brain region that inhibition leads to aggression, thus explaining, at least partially, the neuronal basis for the behavioral abnormality. Taken together, our study indicates that TARP γ-8 expression level is associated with ASPD, and that the TARP γ-8 knockout mouse is a valuable animal model for studying this psychiatric disease.

Reduced cortical gray matter integrity and cognitive abilities are among core deficits in schizophrenia. We hypothesized that higher allostatic load (AL) that accounts for exposure to chronic stress is a contributor to structural and cognitive deficits in schizophrenia. One hundred and sixty-seven schizophrenia patients who were on average with normal weight, normal systolic, and diastolic blood pressure and 72 healthy controls were enrolled in the study. Group differences in subclinical cardiovascular, metabolic, immune, and neuroendocrine biological markers as indexed by AL and contribution of AL components to the structural and cognitive deficits in schizophrenia were explored. Compared with controls, schizophrenia patients who were normotensive, normoweight, and had low total cholesterol levels still had significantly higher AL mainly due to lower high-density lipoprotein cholesterol and higher heart rate, waist-hip ratio, hemoglobinA1c, hypersensitive C-reactive protein, and overnight-urine cortisol levels. Patients also had decreased whole-brain mean cortical thickness, and lower cognition assessed by the MATRICS consensus cognitive battery. AL was inversely correlated with mean cortical thickness and cognition in schizophrenia, while none of these relationships existed in controls. Mediation analyses showed the effect of AL on cognitive deficits in schizophrenia was significantly mediated by cortical thinning, and the most significant mediating cortical area was the left superior frontal gyrus. Cortical thickness may act as a mediator between AL and cognitive deficits in schizophrenia. Early intervention strategies to reduce cortical thinning and cognitive dysfunction in schizophrenia should target specific aspects of their high AL in addition to weight gain, hypertension and high cholesterol levels.

Supplemental material, sj-docx-1-anp-10.1177_00048674211009595 for An independent, replicable, functional and significant risk variant block at intron 3 of CACNA1C for schizophrenia by Zuxing Wang, Wenzhong Chen, Yuping Cao, Yikai Dou, Yingmei Fu, Yong Zhang, Xingqun Luo, Longli Kang, Na Liu, Yun Stone Shi, Chiang-shan R Li, Yifeng Xu, Xiaoyun Guo and Xingguang Luo in Australian & New Zealand Journal of Psychiatry

Accumulating evidence indicates that a dysregulated kynurenine (KYN) pathway (KP) metabolism may play an important role in the pathogenesis of both schizophrenia and metabolic syndrome (MS). However, the underlying mechanisms remain poorly understood. Here, we aimed to evaluate the potential roles of KP in the pathogenesis of MS in schizophrenia. A total of 160 schizophrenia patients and 70 healthy controls were enrolled in this study. KP metabolites were quantified, and MS scores were calculated, for comparisons between patients and controls. Associations among the indices were explored in both groups. Multiple linear regression analyses were performed to investigate the effects of KP metabolites on MS factors. We observed a significantly higher MS score, lower levels of all KP metabolites, and higher nicotinamide adenine dinucleotide (NAD+)/quinolinic acid (QUNA) in patients than in controls (all p

Animal and neuroimaging studies suggest that the volume of the motor-circuit region decreases in tardive dyskinesia (TD). This study examined the differences in functional connectivity within the motor circuit of patients with schizophrenia with and without TD to further clarify how the dysfunction is related to the pathogenesis of TD.Functional magnetic resonance images were taken of 56 schizophrenic patients with TD (TD group), 64 without TD (non-TD group), and 68 healthy controls (HC group). The motor-circuit area was selected as the seed region for a whole brain resting-state functional connectivity (rsFC) analysis. Psychopathological symptoms and TD severity were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Group differences and correlations among 18 brain regions of interest (e.g., the global strength of connectivity between two regions) were analyzed.The analysis of variance results were as follows: The three groups exhibited rsFC losses in the left primary motor cortex, bilateral parietal cortices, right postcentral gyrus, right putamen, right superior parietal lobule, right supplementary motor area and bilateral thalami (false discovery rate,p0.05). The TD group showed a significant rsFC loss between the right postcentral gyrus and the inferior frontal gyrus of the left triangular part when compared with the non-TD group (AlphaSim, p0.001), which was negatively correlated with the AIMS total score (r=-0.259, p = 0.03).These findings may suggest dysfunction of the postcentral and inferior frontal gyri of the triangular part in patients with schizophrenia and TD.

Background Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson’s disease (PD). Recent studies have reported specific effects of kinectin 1 gene (KTN1) variants on the putamen GMV. Objective To examine the relationship of KTN1 variants, KTN1 mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD. Methods We examined the associations between PD and a total of 1847 imputed KTN1 single nucleotide polymorphisms (SNPs) in one discovery sample [2,000 subjects with PD vs. 1,986 healthy controls (HC)], and confirmed the nominally significant associations (p < 0.05) in two replication samples (900 PD vs. 867 HC, and 940 PD vs. 801 HC, respectively). The regulatory effects of risk variants on the KTN1 mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of KTN1 mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts. Results Six replicable and two non-replicable KTN1-PD associations were identified (0.009 ≤ p ≤ 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 ≤ p ≤ 0.049) and putamen GMVs (19.08 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10–51 ≤ p ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the KTN1 mRNA expression in the putamen or SNc (0.021 ≤ p ≤ 0.046). The KTN1 mRNA was abundant in the putamen and/or SNc across five independent cohorts and differentially expressed in the SNc between PD and HC in one cohort (p = 0.047). Conclusion There was a consistent, significant, replicable, and robust positive relationship among the KTN1 variants, PD risk, KTN1 mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and KTN1 mRNA expression in SNc, suggesting that KTN1 may play a functional role in the development of PD.

MicroRNA (miR)-181b-5p is considered to be involved in the pathogenesis of schizophrenia, and one of its regulatory target genes BCL-2 (B-cell lymphoma 2) is suggested to associate with cognition of schizophrenia. Cognitive deficit is a core trait of schizophrenia. However, it remains unclear whether miR-181b-5p affects cognition and its possible pathway in schizophrenia. We hypothesized that miR-181b-5p affects cognition by targeting BCL-2 mRNA and downregulating BCL-2 protein expression in schizophrenia patients. In this study, first-episode patients with schizophrenia (FEPS, n = 123) and age- and gender-matched healthy controls (HCs, n = 50) were enrolled in Chinese populations. Expression levels of miR-181b-5p and BCL-2 mRNA in peripheral whole blood were measured with quantitative real-time PCR (Q-PCR) and BCL-2 protein in plasma were measured with Enzyme Linked Immunosorbent Assay (ELISA). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS), cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Peripheral blood miR-181b-5p expression level was significantly upregulated (p = 0.001) whereas BCL-2 mRNA and BCL-2 protein levels were significantly downregulated (p = 0.002, p = 0.023 respectively) in the FEPS compared with those in the HCs. The miR-181b-5p level was negatively (p = 0.005), whereas the BCL-2 mRNA level was positively (p < 0.001), correlated with working memory in FEPS. Mediating effect analysis showed that the effect of miR-181b-5p on working memory in the FEPS was exerted via targeting BCL-2 mRNA. MiR-181b-5p in combination with BCL-2 mRNA might be suggested as potential biomarker for schizophrenia in our discovery sample. In conclusion, overexpressed miR-181b-5p may affect cognitive function in patients with schizophrenia.

The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely implicated in the etiological processes of substance use disorders (SUD). Here, we aimed to identify robust and reliable associations between KTN1 SNPs and SUD across multiple samples. We examined the associations between SUD and KTN1 SNPs in four independent population-based or family-based samples (n = 10,209). The potential regulatory effects of the risk alleles on the putamen GMVs, the effects of alcohol, nicotine, marijuana and cocaine on KTN1 mRNA expression, and the relationship between KTN1 mRNA expression and SUD were explored. We found that a total of 23 SNPs were associated with SUD across at least two independent samples (1.4 × 10-4 ≤ p ≤ 0.049), including one SNP (rs12895072) across three samples (8.8 × 10-3 ≤ p ≤ 0.049). Four other SNPs were significantly or suggestively associated with SUD only in European-Australians (4.8 × 10-4 ≤ p ≤ 0.058). All of the SUD-risk alleles of these 27 SNPs increased (β > 0) the putamen GMVs and represented major alleles (f > 0.5) in Europeans. Twenty-two SNPs were potentially biologically functional. Alcohol, nicotine and cocaine significantly affected the KTN1 mRNA expression, and the KTN1 mRNA was differentially expressed between nicotine or cocaine dependent and control subjects. We concluded that there was a replicable and robust relationship among the KTN1 variants, KTN1 mRNA expression, putamen GMVs, molecular effects of substances, and SUD, suggesting that some risk KTN1 alleles might increase kinectin 1 expression in the putamen, altering putamen structures and functions, and leading to SUD.

Bipolar disorder (BD) is often associated with significant functional impairment. However, there is currently no valid and reliable instrument for this variable that is both brief and easy to administer in China. We thus aimed to evaluate the psychometric properties of the Chinese version of the Functioning Assessment Short Test (FAST) in Chinese adults with BD.In this sample of adult subjects, 176 with BD and 53 healthy controls were included. The Chinese version of the FAST, the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Global Assessment Functioning (GAF) were administered, and the psychometric analysis of the FAST was conducted.The internal consistency (Cronbach's alpha) was 0.89 and 0.88 for the FAST at the baseline and week 1, respectively. Four domains (occupational functioning, cognitive functioning, interpersonal relationship and financial issues) at baseline had high item-total correlations. The FAST assessments at baseline and week 1 were highly correlated, indicating high test-retest reliability. The FAST total score was strongly associated with GAF total scores at week 0 (r = -0.952, p 0.001), HDRS (r = 0.575, p 0.001) and YRMS (r = 0.394, p 0.001) and at week 1 (r = -0.945, p 0.001; r = 0.582, p 0.001; r = 0.363, p 0.001), respectively, suggesting high concurrent validity. The FAST showed four dimensional measurement properties in exploratory factor analysis at baseline.The Chinese version of the FAST has satisfactory psychometric properties in terms of validity and reliability in Chinese adults with BD.

Early alcohol, tobacco and drug use prior to 18 years old are comorbid and correlated. This study included 6239 adults with major depressive disorder (MDD) in the past year and 72,010 controls from the combined data of 2013 and 2014 National Survey on Drug Use and Health (NSDUH). To deal with multicollinearity existing among 17 variables related to early alcohol, tobacco and drug use prior to 18 years old, we used principal component analysis (PCA) to infer PC scores and then use weighted multiple logistic regression analyses to estimate the associations of potential factors and PC scores with MDD. The odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. The overall prevalence of MDD was 6.7%. The first four PCs could explain 57% of the total variance. Weighted multiple logistic regression showed that PC 1 (a measure of psychotherapeutic drugs and illicit drugs other than marijuana use), PC 2 (a measure of cocaine and hallucinogens), PC 3 (a measure of early alcohol, cigarettes, and marijuana use), and PC 4 (a measure of cigar, smokeless tobacco use and illicit drugs use) revealed significant associations with MDD (OR = 1.12, 95% CI = 1.08–1.16, OR = 1.08, 95% CI = 1.04–1.12, OR = 1.13, 95% CI = 1.07–1.18, and OR = 1.15, 95% CI = 1.09–1.21, respectively). In conclusion, PCA can be used to reduce the indicators in complex survey data. Early alcohol, tobacco and drug use prior to 18 years old were found to be associated with increased odds of adult MDD.

The human receptor-type protein-tyrosine phosphatase kappa ( PTPRK ) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p −6 ) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10 −2 and 5.18 × 10 −3 , respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10 −2 ) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10 −4 ), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10 −3 ), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10 −3 ), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10 −3 ). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10 −5 ). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

Attention deficit hyperactivity disorder (ADHD) occurs more frequently and manifests with greater symptom severity in men than in women. Although studies have implicated basal ganglia dysfunction, the functional connectivity (FC) of the dorsal striatum (DS), particularly in terms of sex differences, has not been fully investigated in ADHD. Here, using resting state fMRI data of a large sample of adults (n = 744; 395 women; 22–36 years) curated from the Human Connectome Project, we performed seed-based correlations for caudate and lentiform nucleus (LN) FC. ADHD symptom severity was quantified with the Achenbach Adult Self-Report ADHD total score as well as inattention and hyperactivity subscores. Imaging data were processed with published routines and evaluated at a corrected threshold. Men showed significantly higher ADHD total score than women. In men, inattention was negatively associated with LN FC with the right superior frontal gyrus. In women, inattention was negatively associated with caudate FC with the right inferior parietal gyrus and positively with LN FC with the left inferior frontal gyrus, and hyperactivity was positively associated with LN FC with a cluster in the dorsal anterior cingulate cortex and supplementary motor area. Sex differences in most of these connectivity patterns were confirmed by slope tests. Further, k-means clustering of FC's identified 3 groups each in men and in women. In men, group 1 showed higher inattention and hyperactivity than both group 2 and 3, and group 2 showed higher inattention than group 3. In women, group 1 showed higher inattention and hyperactivity than group 3 and higher inattention than group 2, and group 2 showed higher hyperactivity than group 3. These findings together suggest sex differences in DS FC as neural markers of ADHD and potentially of ADHD subtypes, with men and women each showing altered FC predominantly in the executive control and ventral attention/saliency networks.

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p = 8.46 × 10 − 4 ) and 11 SNPs were associated with AAO (top SNP rs1354269 with p = 2.87 × 10 − 3 ). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk ( p = 1.7 × 10 − 2 and 2.71 × 10 − 2 ; respectively) and AAO ( p = 1.85 × 10 − 3 and 6.06 × 10 − 3 ; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.

Putamen is enriched with dopamine and associated with dopamine-related phenotypes including many neuropsychiatric and neurodegenerative disorders that manifest with motor impairment, impulsive behavior, and cognitive deficits. The gray matter volume of the putamen is age-dependent and genetically controlled. In most neuropsychiatric and neurodegenerative disorders, including Parkinson’s spectrum disorders, Huntington’s disease, dementia with Lewy bodies, Alzheimer’s disease, multiple sclerosis, attention deficit hyperactivity disorder, developmental dyslexia, and major depression, the putamen volume is significantly reduced. On the other hand, in individuals with bipolar disorder, schizophrenia spectrum disorders, especially neuroleptics-medicated patients with schizophrenia, autism spectrum disorders, obsessive-compulsive spectrum disorders, and cocaine/amphetamine dependence, the putamen volume is significantly enlarged. Therefore, the putamen volume may serve as a structural neural marker for many neuropsychiatric and neurodegenerative disorders and a predictor of treatment outcomes in individuals afflicted with these conditions. We provided an overview of the genetic bases of putamen volume and explored potential mechanisms whereby altered putamen volume manifests in these neuropsychiatric and neurodegenerative conditions, with a specific focus on dopaminergic processes.

Background Major depression disorder (MDD) is often associated with cognitive impairment. The development of an accurate and effective battery to measure cognitive deficit is necessary for both research and clinical practice in MDD. Our study was designed to test the psychometric properties of the MATRICS Consensus Cognitive Battery (MCCB) in patients with MDD. Method Forty-eight patients with MDD, forty-three euthymic patients with bipolar disorder (BD) and thirty-two remitted patients with schizophrenia (SCH) were recruited from Tianjin Anding Hospital in Tianjin, China. The MCCB, the Montreal Cognitive Assessment (MoCA) and the Hamilton Depression Rating Scale-17 (HDRS-17) were administered to assess cognitive impairment and depressive symptoms at both baseline and one month later. Result Our findings showed that the MCCB had good internal consistency and acceptable reliability in Chinese MDD patients. Our findings revealed a high correlation between the MCCB and the MoCA, indicating good concurrent validity of the MCCB. Furthermore, the MCCB showed high discriminant ability between MDD patients and healthy controls, and a principal component analysis of the MCCB in MDD patients revealed four domains with acceptable internal structure. Limitations We did not consider confounding factors, such as the course, severity of symptoms and medication treatments, which might bias the cognitive assessment. In addition, the use of the MoCA as a reference scale for mild cognitive impairment could weaken the concurrent validity of the MCCB in MDD patients. Conclusion Our findings demonstrated that the MCCB may be clinically useful as a cognitive impairment rating battery in Chinese patients with MDD.

Accumulating evidence has shown that N-methyl-D-aspartate (NMDA) glutamate receptors (NMDAR) are implicated in the pathophysiology of neurological and psychiatric disorders, and that patients with NMDAR antibody encephalitis develop psychopathological symptoms. Therefore, we hypothesized that NMDAR antibodies play a key role in the etiology of schizophrenia. In this study, we enrolled 110 first-episode patients with schizophrenia (FEP) and 50 healthy controls (HC). Cognitive function and psychopathology were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. NMDAR antibody levels were measured using enzyme-linked immunosorbent assay. Our results showed that FEP with schizophrenia exhibited cognitive deficits in all domains of the MCCB and had elevated levels of serum anti-NMDAR antibody compared with the healthy controls (9.2 ± 3.5 vs. 7.3 ± 2.9 ng/ml, t = 3.10, p = 0.002). Furthermore, serum antibody levels were positively correlated with PANSS positive, negative and total score, and inversely correlated with performances of verbal learning and memory, working memory, speed of processing and MCCB total score in the patient group. These results indicate that elevated levels of NMDAR antibody may play a role in the pathogenesis of schizophrenia, leading to NMDAR dysfunction, thereby inducing symptoms of psychosis and cognitive impairment. Therefore, NMDAR antibodies may serve as a biomarker and provide a new avenue for treatment of schizophrenia.

BACKGROUND Accumulating evidence has shown that brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of schizophrenia. Moreover, BDNF genetic variants, especially the Val66Met polymorphism, may influence specific aspects of human cognition. This study aimed to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and cognitive impairments in patients with schizophrenia in a Han Chinese population. METHODS Four polymorphisms (rs6265, rs12273539, rs10835210, and rs2030324) of the BDNF gene were analyzed in a case-control study of 1,887 Han Chinese individuals (844 patients meeting DSM-IV diagnosis of schizophrenia and 1,043 healthy controls). Cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in 598 patients and 434 controls. The current study was conducted from 2008 to 2011. RESULTS Significant differences in the genotype and allele frequencies between patients and controls were observed only for rs10835210 (both P < .05). Further, we found that the rs10835210 polymorphism had a significant effect on language performance only in schizophrenia (P < .05). However, BDNF rs12273539 played a stronger role in cognitive performance among both patients and healthy controls, especially on attention (P < .001) and the RBANS total score (P < .01). CONCLUSIONS These findings suggest the role of these BDNF gene variants in susceptibility to schizophrenia and in some aspects of cognitive function.

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Many of these lncRNAs have regulatory functions and have recently emerged as major players in governing fundamental biological processes. Here we review the definition, distribution, identification, databases, analysis, classification and functions of lncRNAs. We also discuss the potential roles of lncRNAs in the etiological processes of psychiatric disorders and the implications for clinical diagnosis and treatment.

Thrombospondin-2 ( THBS 2) and Thrombospondin-4 ( THBS 4) play an important role in cancer development and progression. However, genetic evidence for their roles in gastric cancer (GC) is lacking. The aim of this study was to explore the association of THBS 2/ THBS 4 polymorphisms with risk and clinicopathological features of GC in a Southeast Chinese population. Eight tagging SNPs in THBS 2 and THBS 4 were genotyped in 761 GC cases and 739 controls from Chinese case–control sets using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS 2/ THBS 4 mRNA expression was studied in 82 human GC tumors and in mouse stomach tissues by real-time PCR. We found that both THBS 2 and THBS 4 were abundantly expressed in mouse stomach. THBS 4 mRNA expression in human stomach was associated with tumor size ( P = 0.002) and tumor-node-metastasis (TNM) ( P = 0.010), and THBS2 mRNA expression was associated with the TNM ( P = 0.010). Patients with the rs77878919^AG genotype were more prone to developing diffuse-type GC. THBS 4 SNPs (rs77878919 and rs7736549) had a modest cumulative effect on the risk of poor prognosis (TNM), with that risk in the highest trend for patients carrying both these unfavorable genotypes. In addition, individuals carrying the THBS4 rs10474606 variant homozygous AA had a modest reduced GC risk. We conclude that THBS2 / THBS4 may be functional in playing important role in GC, which was supported by the evidence of the mRNA overexpression in GC and the modest associations of THBS2/THBS4 polymorphisms to GC. These findings might be useful for risk assessment and prognosis prediction of GC.

Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia.77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects.Patients with schizophrenia showed significantly lower levels of PPI at the 120 ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls.PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study.