Cognitive Deficits In Schizophrenia Research Articles

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine 'modulation bias' in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks.

The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.

Efficacy and auditory biomarker analysis of fronto-temporal transcranial direct current stimulation (tDCS) in targeting cognitive impairment associated with recent-onset schizophrenia: study protocol for a multicenter randomized double-blind sham-controlled trial

BackgroundIn parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial direct current stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear.MethodThe study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS.DiscussionBesides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct a randomized controlled trial (RCT) with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia.Trial registrationClinicalTrials.gov NCT05440955. Prospectively registered on July 1st, 2022.

Aberrant hippocampus and amygdala morphology associated with cognitive deficits in schizophrenia.

Working memory deficits are thought to be a primary disturbance in schizophrenia. We aimed to identify differences in morphology of the hippocampus and amygdala in patients with schizophrenia compared with healthy controls (HCs), and in patients who were either neuropsychologically near normal (NPNN) or neuropsychologically impaired (NPI). Morphological disturbances in the same subfields of the hippocampus and amygdala, but of greater magnitude in those with NPI, would strengthen evidence for the centrality of these limbic regions and working memory deficits in the pathogenesis of schizophrenia. We acquired anatomical MRIs in 69 patients with schizophrenia (18 NPNN, 46 NPI) and 63 age-matched HC participants. We compared groups in hippocampus and amygdala surface morphologies and correlated morphological measures with clinical symptoms and working memory scores. Schizophrenia was associated with inward deformations of the head and tail of the hippocampus, protrusion of the hippocampal body, and widespread inward deformations of the amygdala. In the same regions where we detected the effects of schizophrenia, morphological measures correlated positively with the severity of symptoms and inversely with working memory performance. Patients with NPI displayed a similar pattern of anatomical abnormality compared to patients with NPNN. Our findings indicate that anatomical abnormalities of the hippocampus relate to working memory performance and clinical symptoms in persons with schizophrenia. Moreover, NPNN and NPI patients may lie on a continuum of severity, both in terms of working memory abilities and altered brain structure, with NPI patients being more severe than NPNN patients in both domains.

Comparison of brain network between schizophrenia and bipolar disorder: A multimodal MRI analysis of comparative studies

ObjectiveCognitive impairment is a shared symptom of Schizophrenia (SCZ) and bipolar disorder (BP), but the underlying neural mechanisms for both remain unclear. We aimed to identify abnormalities in the structural and functional brain network of patients with SCZ and BP. MethodsThe study included 69 patients with SCZ, 40 with BP, and 63 healthy controls (HC). After neurocognitive function assessment, resting-state functional magnetic resonance imaging and diffusion tensor imaging were acquired respectively. We compared the network of structural connectivity (SC) and functional connectivity (FC) among the three groups and performed graph theoretical analyses. The SC-FC coupling was calculated, and the correlations between the cognitive function scores and network properties were ascertained. ResultsThe BP group showed significantly higher indicators in subnetworks and graph theory analysis than SCZ and HC. Several brain regions, such as the inferior parietal lobe, exhibited differences among all pairwise comparisons and showed significant correlations with cognitive scores in both SCZ and BP. SC-FC coupling did not significantly differ between the three groups but showed close associations with clinical performance. Interestingly, the direction of correlations between the network properties and cognition tends to present the opposite between SCZ and BP, especially regarding the working memory, attention, and language sections. ConclusionsThe FC and SC network of the SCZ group appeared more inefficient and disconnected than BP. The network demonstrated to be closely but differently associated with cognitive function at both local and global levels, indicating the potentially separated pathologies of cognition deficits in SCZ and BP.

Cognitive and arginine metabolic correlates of temporal dysfunction in the MIA rat model of schizophrenia risk.

As a hallmark characteristic of schizophrenia, abnormal perception of time is thought to arise from cognitive impairment; however, the absence of translational models indexing this pathological relationship creates barriers to understanding the functional and biological bases of timing impairments. Here, we investigate the relationship between timing and cognition using the maternal immune activation (MIA) rat model of schizophrenia. We additionally investigate the role of prefrontal cortex L-arginine metabolism in these processes via high-performance liquid chromatography and liquid chromatography/mass spectrometry. Results revealed that MIA rats exhibit greater underestimation of interval durations (2-8 s); greater underestimation corresponded with declines in sustained attention capacity. Working memory impairments were not found to contribute to timing deficits. These findings represent the first direct identification of a timing-attention relationship within rodents and are discussed with respect to the dopamine hypothesis of temporal pace. We also found that MIA exposure altered aspects of arginine metabolism as observed in schizophrenia, and we present preliminary evidence suggesting that these changes have functional consequences for cognition. These findings support the MIA rat model as a valuable tool for future investigations exploring the biological instantiation of interrelated timing and cognitive deficits in schizophrenia. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prospects for Neurotrophic Factor-Based Early Intervention in Schizophrenia: Lessons Learned from the Effects of Antipsychotic Drugs on Cognition, Neurogenesis, and Neurotrophic Factors.

Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcomes. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that making drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning, and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests a deficit in a wide spectrum of neurotrophic factors in schizophrenia. Since schizophrenia is considered a neurodevelopmental disorder, early intervention with neurotrophic factors may be more effective in ameliorating the cognitive deficits and psychopathological symptoms associated with this pathology. In this context, results from initial clinical trials with neurotrophic factors and their future potential to improve cognition and psychosocial functioning in schizophrenia are discussed.

Correlation of Health-Related Quality of Life with Negative Symptoms Assessed with the Self-Evaluation of Negative Symptoms Scale (SNS) and Cognitive Deficits in Schizophrenia: A Cross-Sectional Study in Routine Psychiatric Care.

(1) Background: Schizophrenia is a severe mental disorder characterized by various symptom groups that tremendously affect health-related quality of life (HRQoL). We aimed to specify whether negative symptoms and cognitive deficits of schizophrenia correlate and can predict HRQoL. (2) Methods: Patients diagnosed with paranoid schizophrenia were invited to participate in the study. Participants were evaluated using the Montreal Cognitive Assessment (MoCA) and the Brief Psychiatric Rating Scale (BPRS) and were asked to fill out the Self-evaluation of Negative Symptoms scale (SNS) and the Medical Outcomes Short Form Survey (SF-36). Pearson's and Spearman's correlations were used to calculate the correlations between cognitive deficits and negative symptoms. We performed the receiver operating characteristic (ROC) analysis for the variables correlated with SF-36 scores. (3) Results: HRQoL correlated significantly with the negative symptoms; however, it did not correlate with cognitive deficits. ROC analysis showed that the abulia subscore of the SNS showed the most significant predictive potential of HRQoL. (4) Conclusions: Negative symptoms correlate more significantly with the HRQoL than cognitive symptoms. The SNS offers the possibility of predicting the HRQoL of patients with schizophrenia and is useful as a screening tool in clinical practice.

Activation of basolateral amygdala to anterior cingulate cortex circuit alleviates MK-801 induced social and cognitive deficits of schizophrenia.

Schizophrenia is a severe psychiatric disorder with a high prevalence worldwide, however, its pathogenesis remains poorly understood. In this study, we used the non-competitive NMDA receptor antagonist MK-801 to induce schizophrenia-like behaviors and confirmed that mice exhibited stereotypic rotational behavior and hyperlocomotion, social interaction defects and cognitive dysfunction, similar to the clinical symptoms in patients. Here, the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) were involved in the schizophrenia-like behaviors induced by MK-801. Furthermore, we confirmed BLA sent glutamatergic projection to the ACC. Chemogenetic and optogenetic regulation of BLA-ACC projecting neurons affected social and cognitive deficits but not stereotypic rotational behavior in MK-801-treated mice. Overall, our study revealed that the BLA-ACC circuit plays a major role and may be a potential target for treating schizophrenia-related symptoms.

Differences in white matter microstructure in first-episode schizophrenia spectrum disorders vs healthy volunteers and their association with cognition

Objective: Both cognitive impairment and alterations in white matter tissue microstructure are well recognised in schizophrenia. We investigated whether differences in white matter microstructure underpin cognitive impairments in patients with first-episode schizophrenia spectrum disorders when controlling for multiple confounding factors. Methods: We employed a cross-sectional study design and compared fractional anisotropy (FA) between individuals diagnosed with first- episode schizophrenia spectrum disorders (FES) (n = 68) and matched healthy controls (n = 120). We conducted multiple analyses of covariance (ANCOVAs) to compare the mean FA values for patients and controls across 27 white matter tracts. We conducted exploratory correlation analyses to determine if white matter tract differences were associated with global cognitive impairment as well as deficits across seven cognitive domains. Results: We found widespread reductions in FA in patients compared to controls, after controlling for confounding variables, such as age, biological sex, education, substances, and childhood adversities. We found a significant positive correlation between the attention/vigilance domain and the splenium of the corpus collosum and external capsule after correction for multiple comparisons. In the control group we found no significant correlations between FA and cognition. Conclusion: Our findings provide a neurobiological basis for attentional cognitive deficits in schizophrenia, highlighting a potential role for the splenium of the corpus collosum and external capsule.

Association of Transferrin Gene Polymorphism with Cognitive Deficits and Psychiatric Symptoms in Patients with Chronic Schizophrenia.

A large amount of recent literature has focused on impaired iron homeostasis in the pathophysiology of schizophrenia. Specifically, microarray analysis has illustrated associations between the transferrin locus and schizophrenia. To elaborate on the effects of transferrin on schizophrenia and its psychiatric phenotypes, our study aimed to investigate whether transferrin gene polymorphism was correlated with cognitive deficits and clinical symptoms in schizophrenia. We recruited 564 patients with chronic schizophrenia and 422 healthy controls (HCs) in a Han Chinese population, collected phenotypic data, and genotyped the rs3811655 polymorphism of the transferrin gene. Our results showed that the rs3811655 polymorphism was related to cognitive performance in both patients and HCs, as well as negative symptoms in patients (all p < 0.05), and patients carrying at least one G-allele showed worsened cognition/severe negative symptoms (all p < 0.05). Further analyses also found that the rs3811655 polymorphism in combination with cognition may exert small but significant contributions to the negative (β = -0.10, t = -2.48, p < 0.05) or total psychiatric symptoms (β = -0.08, t = -1.92, p < 0.05) in patients. Our findings indicated that the rs3811655 polymorphism may be implicated in the cognitive deficits of schizophrenia and HCs as well as psychiatric symptoms in patients, which suggested the possible iron regulatory mechanism in the pathology of schizophrenia.

Stimulating learning: A functional MRI and behavioral investigation of the effects of transcranial direct current stimulation on stochastic learning in schizophrenia

Transcranial direct current stimulation (tDCS) of the medial prefrontal cortex (mPFC) is under clinical investigation as a treatment for cognitive deficits. We investigate the effects of tDCS over the mPFC on performance SSLT in individuals with schizophrenia, and the underlying neurophysiological effect in regions associated with learning values and stimulus-outcome relationships. In this parallel-design double-blind pilot study, 49 individuals with schizophrenia, of whom 28 completed a fMRI, were randomized into active or sham tDCS stimulation groups. Subjects participated in 4 days of SSLT training (days 1, 2, 14, 56) with tDCS applied at day-1, and during a concurrent MRI scan at day-14. The SSLT demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 and at day-56. Active tDCS was associated with increased insular activity, and reduced amygdala activation. tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia, with this study being the first to show a longer-term effect on SSLT.

Fingolimod ameliorates schizophrenia-like cognitive impairments induced by phencyclidine in male rats.

Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway. This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.

Plasma metabolomics of schizophrenia with cognitive impairment: A pilot study.

Schizophrenia (SCZ) acts as a complex and burdensome disease, in which the functional outcome can be validly predicted by cognitive impairment, as one of the core features. However, there still lack considerable markers of cognitive deficits in SCZ. Based on metabolomics, it is expected to identify different metabolic characteristics of SCZ with cognitive impairment. In the present study, 17 SCZ patients with cognitive impairment (CI), 17 matched SCZ patients with cognitive normal (CN), and 20 healthy control subjects (HC) were recruited, whose plasma metabolites were measured using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The result of metabolic profiling indicated the identification of 46 differentially expressed metabolites between HC, CN, and CI groups, with 7 differentially expressed metabolites between CN and CI groups. Four differential metabolites (imidazolepropionic acid, Homoserine, and Aspartic acid) were repeatedly found in both screenings, by which the formed biomarker panel could discriminate SCZ with cognitive impairment from matched patients (AUC = 0.974) and health control (AUC = 0.841), respectively. Several significant metabolic pathways were highlighted in pathway analysis, involving Alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, and Citrate cycle (TCA cycle). In this study, several differentially expressed metabolites were identified in SCZ with cognitive impairment, providing novel insights into clinical treatment strategies.

Network hub centrality and working memory performance in schizophrenia

Cognitive impairment, and working memory deficits in particular, are debilitating, treatment-resistant aspects of schizophrenia. Dysfunction of brain network hubs, putatively related to altered neurodevelopment, is thought to underlie the cognitive symptoms associated with this illness. Here, we used weighted degree, a robust graph theory metric representing the number of weighted connections to a node, to quantify centrality in cortical hubs in 29 patients with schizophrenia and 29 age- and gender-matched healthy controls and identify the critical nodes that underlie working memory performance. In both patients and controls, elevated weighted degree in the default mode network (DMN) was generally associated with poorer performance (accuracy and reaction time). Higher degree in the ventral attention network (VAN) nodes in the right superior temporal cortex was associated with better performance (accuracy) in patients. Degree in several prefrontal and parietal areas was associated with cognitive performance only in patients. In regions that are critical for sustained attention, these correlations were primarily driven by between-network connectivity in patients. Moreover, a cross-validated prediction analysis showed that a linear model using a summary degree score can be used to predict an individual’s working memory accuracy (r = 0.35). Our results suggest that schizophrenia is associated with dysfunctional hubs in the cortical systems supporting internal and external cognition and highlight the importance of topological network analysis in the search of biomarkers for cognitive deficits in schizophrenia.

Thalamocortical connectivity and its relationship with symptoms and cognition across the psychosis continuum.

Coordination between the thalamus and cortex is necessary for efficient processing of sensory information and appears disrupted in schizophrenia. The significance of this disrupted coordination (i.e. thalamocortical dysconnectivity) to the symptoms and cognitive deficits of schizophrenia is unclear. It is also unknown whether similar dysconnectivity is observed in other forms of psychotic psychopathology and associated with familial risk for psychosis. Here we examine the relevance of thalamocortical connectivity to the clinical symptoms and cognition of patients with psychotic psychopathology, their first-degree biological relatives, and a group of healthy controls. Patients with a schizophrenia-spectrum diagnosis (N = 100) or bipolar disorder with a history of psychosis (N = 33), their first-degree relatives (N = 73), and a group of healthy controls (N = 43) underwent resting functional MRI in addition to clinical and cognitive assessments as part of the Psychosis Human Connectome Project. A bilateral mediodorsal thalamus seed-based analysis was used to measure thalamocortical connectivity and test for group differences, as well as associations with symptomatology and cognition. Reduced connectivity from mediodorsal thalamus to insular, orbitofrontal, and cerebellar regions was seen in schizophrenia. Across groups, greater symptomatology was related to less thalamocortical connectivity to the left middle frontal gyrus, anterior cingulate, right insula, and cerebellum. Poorer cognition was related to less thalamocortical connectivity to bilateral insula. Analyses revealed similar patterns of dysconnectivity across patient groups and their relatives. Reduced thalamo-prefrontal-cerebellar and thalamo-insular connectivity may contribute to clinical symptomatology and cognitive deficits in patients with psychosis as well as individuals with familial risk for psychotic psychopathology.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Sexual dimorphism in the relationship between Forkhead-Box P2 and BMI with cognitive deficits in schizophrenia.

FOXP2, cognitive deficits, and schizophrenia are associated with neurodegenerative pathophyisiology. Mounting evidence suggests that body mass index (BMI) and FOXP2 may contribute to cognitive deficits in schizophrenia. However, the sex difference in the contribution of FOXP2 and BMI, as well as their potential interaction with cognitive deficits in schizophrenia, have not been investigated. A total of 867 schizophrenia patients and 402 controls were recruited. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The polymorphism rs10447760 of the FOXP2 gene was genotyped. Male schizophrenia patients had superior language performance compared to female patients (F = 17.83; pBonferroni < 0.0001). BMI was positively associated with language scores in male patients with schizophrenia (ß = 0.60, t = 3.30, p = 0.001), as well as in patients with schizophrenia who carried the FOXP2 rs10447760 CC genotype (ß = 0.53, t = 3.16, p = 0.002). Interestingly, this association was only found in male patients with schizophrenia who also carried the FOXP2 rs10447760 CC genotype (ß = 0.63, t = 3.44, p = 0.001). Our study reveals a sex difference in the language deficits of schizophrenia patients and shows sexual dimorphism in the contribution of FOXP2, BMI, and their interaction to cognitive deficits in patients with schizophrenia.

Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST) as a screening tool for evaluation of cognitive deficits in schizophrenia

Cognitive deficit is one of the core features of schizophrenia and is associated with poor functional outcomes. There is a lack of validated criteria to screen and monitor cognitive deficits in schizophrenia. This study aimed to evaluate the concurrent validity and sensitivity of MoCA (Montreal Cognitive Assessment) and DSST (Digit Symbol Substitution Test) in identifying cognitive deficits in Schizophrenia comparing with a comprehensive MCCB [MATRICS (Measurement And Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery] equivalent battery. We did clinical and cognitive assessments on 30 patients with schizophrenia and 30 age and gender-matched healthy controls. The Cronbach's Alpha of MoCA was 0.839, and on adding the DSST, it increased to 0.859. In stepwise binary logistic regression, adding DSST to MoCA improved the prediction of cognitive impairment as defined by a comprehensive battery with 86.7% classification accuracy. Receiver operating characteristic curve analysis suggested a score of 25 of MoCA and 59 of DSST as an optimal cut-off in identifying severe cognitive deficits with an additional MoCA cut-off of 27 for identifying mild cognitive deficits. Combined MoCA and DSST is a sensitive and quick method to screen for neurocognitive deficits in schizophrenia.

Exploring DNA methylation within the CYP17A gene as a potential mediator between childhood adversity and stress-related phenotypes in schizophrenia

IntroductionStress caused by childhood adversity (CA) is known to contribute to schizophrenia risk and symptoms. Its effects might be mediated by epigenetic mechanisms, specifically DNA methylation (meDNA) within relevant genes, and predominantly influence the hippocampus and prefrontal cortex (PFC). CYP17A1 is a candidate, as it situates within a schizophrenia risk locus and is involved in glucocorticoid synthesis.ObjectivesTo explore meDNA within CYP17A and its relations to hippocampus- and PFC-dependent schizophrenia symptoms: depression and deficits of declarative memory and executive functions.MethodsWe assessed meDNA at each CpG within a CYP17A fragment (chr10:104594471-104595887, hg19) in blood of 66 schizophrenia patients using the third-generation sequencing. Immediate memory, depression, cognitive shifting and cognitive inhibition (CI) were assessed with the RAVLT, PANSS, TMT-B and Stroop word-color test, respectively. ANCOVA and regression models adjusted for sex and age were applied to explore the relations between the phenotypes, local haplotype, meDNA and CA, defined as the presence of parental alcoholism or psychiatric illness.ResultsMeDNA at CpG-SNP rs3781286 correlated with CI (corrected p=0.01). However, there were no main or interaction effects of CA either on meDNA at this site or on CI. Both CI and meDNA associated with haplotype, but subsequent analysis showed that meDNA did not mediate the relation between haplotype and CI.ConclusionsOur findings suggest that CYP17A associates with PFC-dependent cognitive deficits in schizophrenia but did not support the hypothesis that CA plays a role in this association via meDNA or any other mechanism. Grant support: 21-15-00124/Russian Science Foundation https://rscf.ru/project/21-15-00124/.DisclosureNo significant relationships.