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Using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), previous study showed significant gender differences for cognitive deficits in immediate and delayed memory in schizophrenia patients. However, RBANS does not include reasoning and problem solving, and social cognition. These cognitive functions can significantly affect the outcomes and daily life in patients. This study examined the gender differences of cognition using the measurement and treatment research to improve cognition in schizophrenia (MATRICS) consensus cognitive battery (MCCB), especially focusing on reasoning and problem solving, and social cognition in schizophrenia patients. The results showed that healthy controls exemplified better cognition than patients in both genders in all examined MCCB scores. Male healthy controls had better reasoning and problem solving and working memory than females, but these gender differences were not presented in schizophrenia patients. Also, male schizophrenia patients showed worse cognition than females on social cognition, processing speed, verbal learning and visual learning. Our results support that male schizophrenia patients had more cognitive impairment than females on reasoning and problem solving, social cognition, processing speed, working memory, verbal learning and visual learning.

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 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk 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. [ABSTRACT FROM AUTHOR]

Aim: Approximately a third of patients with schizophrenia fail to adequately respond to antipsychotic medications, a condition known as treatment resistance (TR). We aimed to assess cognitive and cortical thickness deficits and their relationship to TR in schizophrenia. Method: We recruited patients with schizophrenia (n = 127), including patients at treatment initiation (n = 45), treatment‐responsive patients (n = 40) and TR patients (n = 42), and healthy controls (n = 83). Clinical symptoms, neurocognitive function, and structural images were assessed. We performed group comparisons, and explored association of cortical thickness and cognition with TR. Results: The TR patients showed significantly more severe clinical symptoms and cognitive impairment relative to the treatment‐responsive group. Compared to healthy controls, 56 of 68 brain regions showed significantly reduced cortical thickness in patients with schizophrenia. Reductions in five regions were significantly associated with TR (reduction in TR relative to treatment‐responsive patients), i.e. in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cognition deficits were also significantly correlated with cortical thickness in these five regions in patients with schizophrenia. Cortical thickness of the right caudal middle frontal gyrus, superior frontal cortex and pars opercularis of the inferior frontal cortex also significantly mediated effects of cognitive deficits on TR. Conclusion: Treatment resistance in schizophrenia was associated with reduced thickness in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cortical abnormalities further mediate cognitive deficits known to be associated with TR. [ABSTRACT FROM AUTHOR]

Schizophrenia results in poor functional outcomes owing to numerous factors. This study provides the first test of a bottom-up causal model of functional outcome in schizophrenia, using neurocognition, vocal emotional cognition, alexithymia, and negative symptoms as predictors of functional outcome. We investigated a cross-sectional sample of 135 individuals with schizophrenia and 78 controls. Using a series of structural equation modelling analyses, a single pathway was generated among scores from the MATRICS Consensus Cognitive Battery (MCCB), vocal emotion recognition test, Toronto Alexithymia Scale (TAS), Brief Negative Symptom Scale, and the Personal and Social Performance Scale. The scores for each dimension of the MCCB in the schizophrenia group were significantly lower than that in the control group. The recognition accuracy for different emotions (anger, disgust, fear, sadness, surprise, and satire, but not calm was significantly lower in the schizophrenia group than in the control group. Moreover, the scores on the three dimensions of TAS were significantly higher in the schizophrenia group than in the control group. On path analysis modelling, the proposed bottom-up causal model showed a strong fit with the data and formed a single pathway, from neurocognition to vocal emotional cognition, to alexithymia, to negative symptoms, and to poor functional outcomes. The study results strongly support the proposed bottom-up causal model of functional outcome in schizophrenia. The model could be used to better understand the causal factors related to the functional outcome, as well as for the development of intervention strategies to improve functional outcomes in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Computerized cognitive remediation therapy (CCRT) is generally effective for the cognitive deficits of schizophrenia. However, there is much uncertainty about what factors mediate or moderate effectiveness and are therefore important to personalize treatment and boost its effects. Method: In total, 311 Chinese inpatients with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia were randomized to receive CCRT or Active control for 12 weeks with four to five sessions per week. All participants were assessed at baseline, post-treatment and 3-month follow-up. The outcomes were cognition, clinical symptoms and functional outcomes. Results: There was a significant benefit in the MATRICS Consensus Cognitive Battery (MCCB) total score for CCRT (F1,258 = 5.62; p = 0.02; effect size was 0.27, 95% confidence interval 0.04–0.49). There were no specific moderators of CCRT improvements. However, across both groups, Wisconsin Card Sort Test improvement mediated a positive effect on functional capacity and Digit Span benefit mediated decreases in positive symptoms. In exploratory analyses younger and older participants showed cognitive improvements but on different tests (younger on Symbol Coding Test, while older on the Spatial Span Test). Only the older age group showed MSCEIT benefits at post-treatment. In addition, cognition at baseline negatively correlated with cognitive improvement and those whose MCCB baseline total score was around 31 seem to derive the most benefit. Conclusions: CCRT can improve the cognitive function of patients with schizophrenia. Changes in cognitive outcomes also contributed to improvements in functional outcomes either directly or solely in the context of CCRT. Age and the basic cognitive level of the participants seem to affect the cognitive benefits from CCRT. [ABSTRACT FROM AUTHOR]

Excessive reactive oxygen species are thought to produce oxidative damage that underlies neurodegeneration and cognitive impairment in several disorders including schizophrenia. The functional Ala-9Val polymorphism of the mitochondrial enzyme manganese superoxide dismutase (MnSOD), which detoxifies superoxide radicals to hydrogen peroxide, has been associated with schizophrenia. However, no study has reported its role in cognitive deficits of schizophrenia as mediated through MnSOD activity. We recruited 923 schizophrenic inpatients and 566 healthy controls and compared them on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), plasma MnSOD activity, and the MnSOD Ala-9Val polymorphism. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that the MnSOD Ala-9Val polymorphism may not contribute directly to the susceptibility to schizophrenia. The Ala variant was associated with worse attention performance among chronic schizophrenic patients but not among normal controls. Plasma MnSOD activity was significantly decreased in patients compared with that in normal controls. Moreover, MnSOD activity among the schizophrenic Ala allele carriers was correlated with the degree of cognitive impairments, especially attention and RBANS total score. We demonstrated an association between the MnSOD Ala-9Val variant and poor attention in schizophrenia. The association between higher MnSOD activity and cognitive impairment in schizophrenia is dependent on the MnSOD Ala-9Val polymorphism. [ABSTRACT FROM PUBLISHER]

The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. [ABSTRACT FROM AUTHOR]

• The TRS group had significantly higher salivary KYNA than the NTRS group, who in turn had higher salivary KYNA than HC. • Higher salivary KYNA was associated with larger choroid plexus volume in TRS patients. • Higher salivary KYNA related to worse cognitive performances worse and higher total PANSS score in TRS patients. • An enlarged choroid plexus was also related to worse cognitive performances and clinical symptoms in TRS patients only. Patients with treatment-resistant schizophrenia (TRS) suffer severe, long-term psychotic symptoms and chronic stress. Salivary kynurenic acid (KYNA) and choroid plexus were evidenced to relate to psychological stress. We hypothesized that TRS patients would have higher salivary KYNA levels than patients who respond to antipsychotics (NTRS) and healthy controls (HC), and increased salivary KYNA levels are associated with clinical phenotypes and choroid plexus volume. A total of 66 HC participants, 53 patients with TRS and 46 with NTRS were enrolled. Salivary KYNA levels were measured by liquid chromatography-tandem mass spectrometry, choroid plexus volume by magnetic resonance imaging, and cognitive functions with the MATRICS Consensus Cognitive Battery. The TRS group had significantly higher salivary KYNA levels than the NTRS group (p = 0.003), who in turn had higher salivary KYNA than HC (p = 0.02). Higher salivary KYNA levels were associated with larger choroid plexus volume (r = 0.48, p = 0.004); lower attention/vigilance (r = -0.44, p = 0.004), verbal learning (r = -0.44, p = 0.004), total MCCB score (r = -0.42, p = 0.005); and a higher total PANSS score (r = 0.48, p = 0.004) in TRS patients. An enlarged choroid plexus also related to worse attention/vigilance (r = -0.39, p = 0.03), verbal learning (r = -0.55, p = 0.001), total MCCB score (r = -0.41, p = 0.02) and clinical symptoms (r = 0.48, p = 0.004) in TRS patients only. We conclude that elevated salivary KYNA levels and associated choroid plexus enlargement are clinically relevant indicators of TRS, with salivary KYNA being particularly valuable as a peripheral marker. Our findings should benefit TRS research and benefit the improvement of personalized treatment. [ABSTRACT FROM AUTHOR]

Background: Cognitive remediation therapy (CRT) and Computerized CRT (CCRT) improve cognition and functioning, but there is no direct evidence of whether there is an advantage of using a computer. This study fills this gap and extends research evidence to the long-term effect of these two treatments in a large sample of Chinese inpatients with a diagnosis of schizophrenia.Method: We conducted a randomized single-blind, follow-up study with participants randomized to receive CCRT (n = 144), CRT (n = 72) or Active control (n = 54) for 12 weeks with 4-5 sessions per week. The main outcome was cognition (MATRICS Consensus Cognitive Battery total score, MCCB), and secondary outcomes were cognitive domains, symptoms and functioning assessed at baseline (0 month), post-treatment (3 months) and follow-up (6, 12 and 18 months).Results: The primary outcome (MCCB total score) improved in both treatment groups which was maintained at 18 months but did not differ between treatment groups. Post hoc analysis demonstrated that the CRT group had an advantage over CCRT for the Trail Making and Symbol Coding Tests (all p < 0.05), which lasted for almost 18 months.Conclusions: Both CCRT and CRT contribute to general cognitive improvements in schizophrenia and the overall efficacy was similar. The effects were maintained for 18th months. Exploratory analyses revealed few differences except that CRT had a processing speed advantage. [ABSTRACT FROM AUTHOR]

Although differential patterns in clinical characteristics have been consistently noted between male and female patients with bipolar disorder (BD), the effect of sex on the hippocampal structure remains unclear. To address this, the present study investigated the effects of BD and sex on the hippocampal structure, and the relationship between the hippocampal structure and cognitive performance. Morphometric and neurocognitive analyses were performed in 91 subjects (patients with BD: male/female = 33/19; normal controls: male/female = 22/17). Patients had significantly decreased left parahippocampal gyrus area and left/right hippocampal volume compared to normal controls. Within the BD group only, female patients presented with smaller right hippocampal volume than males. In the Spatial Span (SS) test (used to assess working memory capacity) and the Maze test (used to evaluate the ability to anticipate), patients demonstrated decreased performance compared to normal controls, with a significant main effect of sex. Left parahippocampal gyrus area and right hippocampal volume were positively correlated with SS and Maze in patients; moreover, right hippocampal volume predicted 17.4% of SS performance variance. These results suggest that there may be a difference between male and female patients with regard to right hippocampal volume, and that female patients may need more attention than males. [ABSTRACT FROM AUTHOR]

S100B, a biomarker of glial dysfunction and blood-brain barrier (BBB) disruption, has been proposed to be involved in the pathophysiology of schizophrenia. In the present study, we aimed at exploring the association of serum S100B levels with cognitive deficits using MATRICS Consensus Cognitive Battery (MCCB) in schizophrenia, by excluding the impact of antipsychotics. Sixty-two unmedicated patients with schizophrenia during their acute phases were divided into a drug-naïve group (n=34) and a drug-free group (n=28). S100B serum concentrations were measured and MCCB was administered to all of the patients. Forty healthy controls donated their blood samples for S100B assessment. The results indicated that serum S100B was significantly elevated in the drug-naive/free acute-stage schizophrenic patients when compared to the healthy controls. In the drug-free group, the serum S100B level was an independent contributor to the global cognitive dysfunctions, particularly for the speed of processing, attention/vigilance, visual learning and reasoning/problem solving subscores. Nevertheless, no significant associations between S100B and MCCB composite score or any cognitive domain subscore were observed in the drug-naïve group. These findings support the hypothesis that glial dysfunction and associated marker protein S100B may contribute to the pathophysiologic development of neurocognitive deficits in the relapsed individuals with schizophrenia. [ABSTRACT FROM AUTHOR]

• Both TD and NTD patients showed higher TLR4 signal pathway activity at baseline but weaker responses to lipopolysaccharide (LPS), as compared to healthy controls. These trends were less pronounced in TD patients than in NTD patients. • In TD patients, TLR4 levels were negatively or positively correlated with MCCB at baseline or after LPS stimulation, respectively. Mounting evidence suggests that the innate immune system is disrupted in schizophrenia patients with tardive dyskinesia (TD); however, the role of the toll-like receptor 4 (TLR4) signaling pathway remains unclear. In this study, we quantified the expression of the monocytic TLR4 signaling pathway using flow cytometry, before and after lipopolysaccharide (LPS) stimulation, in chronic schizophrenia patients with (n = 61) and without TD (NTD, n = 61) and healthy controls (HCs, n = 74). Psychopathological symptoms, the severity of TD, and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and MATRICS Consensus Cognitive Battery (MCCB), respectively. 1) Both TD and NTD patients showed higher TLR4 signaling pathway activity at baseline than that in HCs, but their responses to LPS were weaker than those in HCs; 2) the alteration of the TLR4 signaling pathway was less severe in TD patients than in NTD patients; 3) TLR4 levels and MCCB scores were negatively correlated at baseline but positively correlated after LPS stimulation in TD patients; 4) there was no correlation between the TLR4 signals and PANSS or AIMS scores. Our findings suggested the TLR4 signaling pathway disturbance might be related to cognitive deficits in schizophrenia patients with TD. [ABSTRACT FROM AUTHOR]

The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. [ABSTRACT FROM AUTHOR]

• Deficits in all domains of cognition and hippocampal volume in patients with treatment-resistant schizophrenia as compared to healthy control group. • Only poorer performances in working memory and smaller total hippocampal volume in patients with treatment-resistant schizophrenia by comparisons with matched treatment-responsive patients. • Working memory deficits and smaller hippocampal volume contribute to higher risk of treatment resistance, but not their interactions. Some patients with schizophrenia do not respond to pharmacotherapy. More severe cognitive dysfunctions have been associated with treatment-resistant schizophrenia (TRS). This study examines cognitive functions and hippocampal volumes in 43 patients with TRS and compared them to 43 treatment-responsive patients (NTRS), matched on age, sex and education, as well as 53 healthy controls (HC). The results showed that there were significant deficits in all domains of cognition and hippocampal volumes in TRS as compared to HC group. However, TRS specific deficits, as indicated by comparisons with matched NTRS, were limited to poorer performance in working memory (p = 0.003) and smaller total hippocampal volume (p = 0.01). Logistic regression analysis showed that working memory deficits [ OR 0.94 (95% CI 0.89–0.98), p = 0.005] and smaller hippocampal volume [ OR 0.89 (95% CI 0.81–0.97), p = 0.01], but not their interactions (p = 0.68), contributed to higher risk of treatment resistance. The findings suggest that treatment-resistance to currently available antipsychotic medications may not be due to global cognitive deficits in these patients, but be associated with specific deficits in working memory and hippocampus deficits in the subgroup of schizophrenia. [ABSTRACT FROM AUTHOR]