Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 167
Filter
1.
Schizophr Res ; 270: 281-288, 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38944974

ABSTRACT

BACKGROUND: The striatum is thought to play a critical role in the pathophysiology and antipsychotic treatment of schizophrenia. Previous studies have revealed abnormal functional connectivity (FC) of the striatum in early-onset schizophrenia (EOS) patients. However, no prior studies have examined post-treatment changes of striatal FC in EOS patients. METHODS: We recruited 49 first-episode drug-naïve EOS patients to have resting-state functional magnetic resonance imaging scans at baseline and after 8 weeks of treatment with antipsychotics, along with baseline scanning of 34 healthy controls (HCs) for comparison purposes. We examined the FC values between each seed in striatal subregion and the rest of the brain. The Positive and Negative Syndrome Scale (PANSS) was applied to measure psychiatric symptoms in patients. RESULTS: Compared with HCs at baseline, EOS patients exhibited weaker FC of striatal subregions with several brain regions of the salience network and default mode network. Meanwhile, FC between the dorsal caudal putamen (DCP) and left supplementary motor area, as well as between the DCP and right postcentral gyrus, was negatively correlated with PANSS negative scores. Furthermore, after 8 weeks of treatment, EOS patients showed decreased FC between subregions of the putamen and the triangular part of inferior frontal gyrus, middle frontal gyrus, supramarginal gyrus and inferior parietal lobule. CONCLUSIONS: Decreased striatal FC is evident, even in the early stages of schizophrenia, and enhance our understanding of the neurodevelopmental abnormalities in schizophrenia. The findings also demonstrate that reduced striatal FC occurs after antipsychotic therapy, indicating that antipsychotic effects need to be accounted for when considering striatal FC abnormalities in schizophrenia.

2.
Asian J Psychiatr ; 98: 104106, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38865883

ABSTRACT

BACKGROUND: In patients with schizophrenia, there is abnormal regional functional synchrony. However, whether it also in patients with adolescent-onset schizophrenia (AOS) remains unclear. The goal of this study was to analyze the regional homogeneity (ReHo) of resting functional magnetic resonance imaging to explore the functional abnormalities of the brain in patients with AOS. METHODS: The study included 107 drug-naive first-episode AOS patients and 67 healthy, age, sex, and education-matched controls using resting-state functional magnetic resonance imaging scans. The ReHo method was used to analyze the imaging dataset. RESULTS: Compared with the control group, the ReHo values of the right inferior frontal gyrus orbital part, right middle frontal gyrus (MFG.R), left inferior parietal, but supramarginal and angular gyri, and left precentral gyrus (PreCG.L) were significantly increased and the ReHo value of the left posterior cingulate cortex/anterior cuneiform lobe was significantly decreased in schizophrenia patients. ROC analysis showed that the ReHo values of the MFG.R and PreCG.L might be regarded as potential markers in helping to identify patients. Furthermore, the PANSS scores in the patient group and the ReHo values showed a positive correlation between MFG.R ReHo values and general scores. CONCLUSIONS: Our results suggested that AOS patients had ReHo abnormalities. The ReHo values of these abnormal regions may serve as potential imaging biomarkers for the identification of AOS patients.

3.
Adv Sci (Weinh) ; : e2400929, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38900070

ABSTRACT

To elucidate the brain-wide information interactions that vary and contribute to individual differences in schizophrenia (SCZ), an information-resolved method is employed to construct individual synergistic and redundant interaction matrices based on regional pairwise BOLD time-series from 538 SCZ and 540 normal controls (NC). This analysis reveals a stable pattern of regionally-specific synergy dysfunction in SCZ. Furthermore, a hierarchical Bayesian model is applied to deconstruct the patterns of whole-brain synergy dysfunction into three latent factors that explain symptom heterogeneity in SCZ. Factor 1 exhibits a significant positive correlation with Positive and Negative Syndrome Scale (PANSS) positive scores, while factor 3 demonstrates significant negative correlations with PANSS negative and general scores. By integrating the neuroimaging data with normative gene expression information, this study identifies that each of these three factors corresponded to a subset of the SCZ risk gene set. Finally, by combining data from NeuroSynth and open molecular imaging sources, along with a spatially heterogeneous mean-field model, this study delineates three SCZ synergy factors corresponding to distinct symptom profiles and implicating unique cognitive, neurodynamic, and neurobiological mechanisms.

4.
Animal Model Exp Med ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741390

ABSTRACT

BACKGROUND: Autism and schizophrenia are environmental risk factors associated with prenatal viral infection during pregnancy. It is still unclear whether behavior phenotypes change at different developmental stages in offspring following the activation of the maternal immune system. METHODS: Sprague-Dawley rats received a single caudal vein injection of 10 mg/kg polyinosinic:polycytidylic acid (poly I:C) on gestational day 9 and the offspring were comprehensively tested for behaviors in adolescence and adulthood. RESULTS: Maternal serum levels of interleukin (IL)-6, IL-1ß and tumor necrosis factor-α were elevated in poly I:C-treated dams. The offspring of maternal poly I:C-induced rats showed increased anxiety, impaired social approach, and progressive impaired cognitive and sensorimotor gating function. CONCLUSION: Maternal immune activation led to developmental specificity behavioral impairment in offspring.

5.
Schizophr Bull ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38754993

ABSTRACT

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) is a prevalent mental disorder that imposes significant health burdens. Diagnostic accuracy remains challenging due to clinical subjectivity. To address this issue, we explore magnetic resonance imaging (MRI) as a tool to enhance SZ diagnosis and provide objective references and biomarkers. Using deep learning with graph convolution, we represent MRI data as graphs, aligning with brain structure, and improving feature extraction, and classification. Integration of multiple modalities is expected to enhance classification. STUDY DESIGN: Our study enrolled 683 SZ patients and 606 healthy controls from 7 hospitals, collecting structural MRI and functional MRI data. Both data types were represented as graphs, processed by 2 graph attention networks, and fused for classification. Grad-CAM with graph convolution ensured interpretability, and partial least squares analyzed gene expression in brain regions. STUDY RESULTS: Our method excelled in the classification task, achieving 83.32% accuracy, 83.41% sensitivity, and 83.20% specificity in 10-fold cross-validation, surpassing traditional methods. And our multimodal approach outperformed unimodal methods. Grad-CAM identified potential brain biomarkers consistent with gene analysis and prior research. CONCLUSIONS: Our study demonstrates the effectiveness of deep learning with graph attention networks, surpassing previous SZ diagnostic methods. Multimodal MRI's superiority over unimodal MRI confirms our initial hypothesis. Identifying potential brain biomarkers alongside gene biomarkers holds promise for advancing objective SZ diagnosis and research in SZ.

6.
Schizophr Bull ; 2024 Apr 14.
Article in English | MEDLINE | ID: mdl-38616054

ABSTRACT

BACKGROUND AND HYPOTHESIS: The synaptic pruning hypothesis posits that schizophrenia (SCZ) and autism spectrum disorder (ASD) may represent opposite ends of neurodevelopmental disorders: individuals with ASD exhibit an overabundance of synapses and connections while SCZ was characterized by excessive pruning of synapses and a reduction. Given the strong genetic predisposition of both disorders, we propose a shared genetic component, with certain loci having differential regulatory impacts. STUDY DESIGN: Genome-Wide single nucleotide polymorphism (SNP) data of European descent from SCZ (N cases = 53 386, N controls = 77 258) and ASD (N cases = 18 381, N controls = 27 969) were analyzed. We used genetic correlation, bivariate causal mixture model, conditional false discovery rate method, colocalization, Transcriptome-Wide Association Study (TWAS), and Phenome-Wide Association Study (PheWAS) to investigate the genetic overlap and gene expression pattern. STUDY RESULTS: We found a positive genetic correlation between SCZ and ASD (rg = .26, SE = 0.01, P = 7.87e-14), with 11 genomic loci jointly influencing both conditions (conjFDR <0.05). Functional analysis highlights a significant enrichment of shared genes during early to mid-fetal developmental stages. A notable genetic region on chromosome 17q21.31 (lead SNP rs2696609) showed strong evidence of colocalization (PP.H4.abf = 0.85). This SNP rs2696609 is linked to many imaging-derived brain phenotypes. TWAS indicated opposing gene expression patterns (primarily pseudogenes and long noncoding RNAs [lncRNAs]) for ASD and SCZ in the 17q21.31 region and some genes (LRRC37A4P, LINC02210, and DND1P1) exhibit considerable variation in the cerebellum across the lifespan. CONCLUSIONS: Our findings support a shared genetic basis for SCZ and ASD. A common genetic variant, rs2696609, located in the Chr17q21.31 locus, may exert differential risk regulation on SCZ and ASD by altering brain structure. Future studies should focus on the role of pseudogenes, lncRNAs, and cerebellum in synaptic pruning and neurodevelopmental disorders.

7.
Neuroimage Clin ; 42: 103603, 2024.
Article in English | MEDLINE | ID: mdl-38588618

ABSTRACT

Antipsychotic drug treatment for schizophrenia (SZ) can alter brain structure and function, but it is unclear if specific regional changes are associated with treatment outcome. Therefore, we examined the effects of antipsychotic drug treatment on regional grey matter (GM) density, white matter (WM) density, and functional connectivity (FC) as well as associations between regional changes and treatment efficacy. SZ patients (n = 163) and health controls (HCs) (n = 131) were examined by structural magnetic resonance imaging (sMRI) at baseline, and a subset of SZ patients (n = 77) were re-examined after 8 weeks of second-generation antipsychotic treatment to assess changes in regional GM and WM density. In addition, 88 SZ patients and 81 HCs were examined by resting-state functional MRI (rs-fMRI) at baseline and the patients were re-examined post-treatment to examine FC changes. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were applied to measure psychiatric symptoms and cognitive impairments in SZ. SZ patients were then stratified into response and non-response groups according to PANSS score change (≥50 % decrease or <50 % decrease, respectively). The GM density of the right cingulate gyrus, WM density of the right superior frontal gyrus (SFG) plus 5 other WM tracts were reduced in the response group compared to the non-response group. The FC values between the right anterior cingulate and paracingulate gyrus and left thalamus were reduced in the entire SZ group (n = 88) after treatment, while FC between the right inferior temporal gyrus (ITG) and right medial superior frontal gyrus (SFGmed) was increased in the response group. There were no significant changes in regional FC among the non-response group after treatment and no correlations with symptom or cognition test scores. These findings suggest that the right SFG is a critical target of antipsychotic drugs and that WM density and FC alterations within this region could be used as potential indicators in predicting the treatment outcome of antipsychotics of SZ.


Subject(s)
Antipsychotic Agents , Magnetic Resonance Imaging , Schizophrenia , Humans , Schizophrenia/diagnostic imaging , Schizophrenia/drug therapy , Schizophrenia/pathology , Schizophrenia/physiopathology , Male , Female , Adult , Magnetic Resonance Imaging/methods , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Gray Matter/diagnostic imaging , Gray Matter/pathology , Gray Matter/drug effects , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/pathology , Middle Aged , Treatment Outcome , White Matter/diagnostic imaging , White Matter/pathology , Young Adult , Neuroimaging/methods , Biomarkers
8.
Article in English | MEDLINE | ID: mdl-38642731

ABSTRACT

Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.


Subject(s)
Anxiety , Disease Models, Animal , HMGB1 Protein , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Microglia , Rats, Sprague-Dawley , Schizophrenia , Animals , Rats , Schizophrenia/therapy , Schizophrenia/chemically induced , Mesenchymal Stem Cell Transplantation/methods , Humans , Female , Anxiety/therapy , HMGB1 Protein/metabolism , Pregnancy , Disks Large Homolog 4 Protein/metabolism , Calcium-Binding Proteins/metabolism , Microfilament Proteins/metabolism , Male , Fetal Blood/cytology , Neuroinflammatory Diseases , Synaptophysin/metabolism , Cord Blood Stem Cell Transplantation/methods , Prenatal Exposure Delayed Effects
9.
Brain Res Bull ; 210: 110927, 2024 May.
Article in English | MEDLINE | ID: mdl-38485004

ABSTRACT

Schizophrenia patients have abnormalities in white matter (WM) integrity in brain regions. S100B has been shown to be a marker protein for glial cells. The atypical antipsychotics have neuroprotective effects on the brain. It is not clear whether antipsychotics can induce S100B changes and improve symptoms by protecting oligodendrocytes. To investigate WM and S100B changes and associations and determine the effect of quetiapine on WM and S100B in schizophrenia patients, we determined serum S100B levels with solid phase immunochromatography and fractional anisotropy(FA)values of 36 patients and 40 healthy controls. Patients exhibited significantly higher serum concentrations of S100B and decreased FA values in left postcentral,right superior frontal,right thalamus, and left inferior occipital gyrus, while higher in right temporal cortex WM compared with healthy controls. Following treatment with quetiapine, patients had decreased S100B and higher FA values in right cerebellum,right superior frontal,right thalamus, and left parietal cortex,and decreased FA values in right temporal cortex WM compared with pre-treatment values. Furthermore, S100B were negatively correlated with PANSS positive scores and positively correlated with FA values in the left postcentral cortex. In addition,the percentage change in FA values in the right temporal cortex was positively correlated with the percentage change in the S100B, percentage reduction in PANSS scores, and percentage reduction in PANSS-positive scores. Our findings demonstrated abnormalities in S100B and WM microstructure in patients with schizophrenia. These abnormalities may be partly reversed by quetiapine treatment.


Subject(s)
Antipsychotic Agents , Schizophrenia , White Matter , Humans , Schizophrenia/diagnostic imaging , Schizophrenia/drug therapy , White Matter/diagnostic imaging , Quetiapine Fumarate/therapeutic use , Diffusion Tensor Imaging/methods , Brain/diagnostic imaging , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , S100 Calcium Binding Protein beta Subunit
10.
Brain Behav ; 14(1): e3333, 2024 01.
Article in English | MEDLINE | ID: mdl-38376021

ABSTRACT

BACKGROUND: Neuroimaging studies have revealed the role of the right dorsolateral prefrontal cortex (DLPFC) in the neurobiological mechanism of obsessive-compulsive disorder (OCD). However, only a few studies have examined the functional connectivity (FC) pattern of the right DLPFC at rest in OCD. OBJECTIVE: The aim of this research is to examine the FC patterns of the right DLPFC at rest in OCD. METHODS: Twenty-eight medication-free patients with OCD and 20 healthy controls underwent resting-state functional magnetic resonance imaging. Seed-based FC and support vector machine (SVM) were used to analyze the imaging data. RESULTS: The patients with OCD showed reduced FC values in the right middle temporal gyrus (MTG), right superior temporal gyrus, right ventral anterior cingulate cortex (vACC), and left Crus II. No brain regions showed a remarkable difference in FC values in patients with OCD after 8 weeks of medication treatment. The reduced right DLPFC-right MTG and right DLPFC-right vACC connectivities were correlated with the clinical symptoms of OCD. SVM results showed that reduced right DLPFC-right MTG connectivity at rest could predict the therapeutic response to OCD medication. CONCLUSIONS: The findings highlight the important role of the right DLPFC in the pathophysiological mechanism of OCD.


Subject(s)
Dorsolateral Prefrontal Cortex , Obsessive-Compulsive Disorder , Humans , Magnetic Resonance Imaging/methods , Gyrus Cinguli/diagnostic imaging , Brain , Prefrontal Cortex/diagnostic imaging , Brain Mapping/methods
11.
Mol Psychiatry ; 2024 Feb 09.
Article in English | MEDLINE | ID: mdl-38336841

ABSTRACT

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

12.
Psychopharmacology (Berl) ; 241(4): 865-874, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38191677

ABSTRACT

RATIONALE: The precise diagnosis and treatment of cognitive impairment remains a major challenge in the field of schizophrenia (SCZ) research. Synaptic dysfunction and loss are thought to be closely related to the occurrence and development of SCZ and may be involved in cognitive dysfunction. OBJECTIVES: The purpose of this study was to investigate whether neuronal pentraxins (NPTXs) plays a role in the etiology of SCZ and provide evidence of its possible therapeutic value a new target for drug development. METHODS: We recruited 275 participants, of whom 148 were SCZ from psychiatric hospital and 127 healthy control (HC) subjects from communities. Plasma concentrations of NPTXs were measured in HC and SCZ at baseline and after 8 weeks of antipsychotic treatment. The MATRICS Cognitive Consensus Battery was used to evaluate cognitive function. Furthermore, the brain is parcellated into 246 subregions using the Brainnetome atlas, and we extracted regional white matter volumes from magnetic resonance images of the SCZ groups. RESULTS: Plasma NPTX2 levels were significantly lower in SCZ compared with HC subjects, but were significantly raised in SCZ after 8 weeks of antipsychotic treatment compared to baseline. In addition, baseline plasma NPTX2 levels were positively correlated with cognitive performance. CONCLUSIONS: These findings indicate that NPTX2 may reveal novel aspects of disease etiology and act as a promising target for new drug development.


Subject(s)
Antipsychotic Agents , Cognitive Dysfunction , Nerve Tissue Proteins , Schizophrenia , Humans , Schizophrenia/diagnosis , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , C-Reactive Protein , Cognition/physiology
13.
Neuropsychopharmacology ; 49(2): 433-442, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37715107

ABSTRACT

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.


Subject(s)
Cation Transport Proteins , Schizophrenia , Humans , Mice , Animals , Genome-Wide Association Study/methods , Genetic Predisposition to Disease/genetics , Dendritic Spines/metabolism , Prefrontal Cortex/metabolism , Cognition , Sensory Gating , Morphogenesis , Polymorphism, Single Nucleotide/genetics , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism
14.
Schizophr Res ; 264: 29-38, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38086110

ABSTRACT

BACKGROUND: The pathophysiological mechanisms of schizophrenia are still unclear. Converging evidence suggests that energy metabolism abnormalities are involved in schizophrenia, and support its role in the pathophysiology of this disease. Lactate plays an important role in energy metabolism. Many studies have reported changes in the levels of lactate in the brain and serum of schizophrenia patients; however, the results from these studies are not consistent. To overcome this limitation, the goal of the present meta-analysis is to analyze the changes in lactate levels in the brain and blood of schizophrenia patients. METHODS: For this systematic review and meta-analysis, we performed a thorough search of relevant literature in the English language, using the MEDLINE, Cochrane, and Embase databases. RESULTS: In the present meta-analysis, 20 studies were scrutinized, including 13 studies on brain lactate levels, which involved 322 schizophrenia patients and 324 healthy individuals as controls. 7 studies on blood lactate levels, involving 234 schizophrenia patients and 238 healthy individuals, were also included. Brain lactate levels were elevated in schizophrenia patients, both in vivo and in post-mortem studies. Nevertheless, blood lactate levels in schizophrenia patients have revealed no statistically significant difference, as compared with control individuals. CONCLUSIONS: In comparison with healthy individuals, schizophrenia patients had higher lactate levels in the brain, rather than in the blood. These findings suggest independent regulatory mechanisms of lactate levels in the brain and peripheral tissues. Abnormal lactate metabolism in the brain may be an important pathological mechanism in schizophrenia.


Subject(s)
Schizophrenia , Humans , Brain , Lactic Acid/metabolism , Research Design
15.
Nat Hum Behav ; 8(2): 361-379, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37945807

ABSTRACT

Anxiety disorders are the most prevalent mental disorders. However, the genetic etiology of anxiety disorders remains largely unknown. Here we conducted a genome-wide meta-analysis on anxiety disorders by including 74,973 (28,392 proxy) cases and 400,243 (146,771 proxy) controls. We identified 14 risk loci, including 10 new associations near CNTNAP5, MAP2, RAB9BP1, BTN1A1, PRR16, PCLO, PTPRD, FARP1, CDH2 and RAB27B. Functional genomics and fine-mapping pinpointed the potential causal variants, and expression quantitative trait loci analysis revealed the potential target genes regulated by the risk variants. Integrative analyses, including transcriptome-wide association study, proteome-wide association study and colocalization analyses, prioritized potential causal genes (including CTNND1 and RAB27B). Evidence from multiple analyses revealed possibly causal genes, including RAB27B, BTN3A2, PCLO and CTNND1. Finally, we showed that Ctnnd1 knockdown affected dendritic spine density and resulted in anxiety-like behaviours in mice, revealing the potential role of CTNND1 in anxiety disorders. Our study identified new risk loci, potential causal variants and genes for anxiety disorders, providing insights into the genetic architecture of anxiety disorders and potential therapeutic targets.


Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Mice , Animals , Genetic Predisposition to Disease/genetics , Genomics , Quantitative Trait Loci/genetics , Anxiety Disorders/genetics
16.
Curr Neuropharmacol ; 22(1): 159-167, 2024.
Article in English | MEDLINE | ID: mdl-36600620

ABSTRACT

BACKGROUND: Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study. METHODS: Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response. RESULTS: At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (p < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time (p < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores (p < 0.05). CONCLUSION: TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.


Subject(s)
Antipsychotic Agents , Schizophrenia , Humans , Antipsychotic Agents/therapeutic use , Schizophrenia/drug therapy , Schizophrenia/metabolism , Olanzapine/therapeutic use , Risperidone/therapeutic use , Quetiapine Fumarate/therapeutic use , Haloperidol/therapeutic use , Perphenazine/therapeutic use , Benzodiazepines/adverse effects , Glucose/therapeutic use , Inflammation/drug therapy
17.
Sci Signal ; 16(814): eadi8645, 2023 12 05.
Article in English | MEDLINE | ID: mdl-38051778

ABSTRACT

Septin proteins are involved in diverse physiological functions, including the formation of specialized cytoskeletal structures. Septin 8 (Sept8) is implicated in spine morphogenesis and dendritic branching through palmitoylation. We explored the role and regulation of a Sept8 variant in human neural-like cells and in the mouse brain. We identified Sept8-204 as a brain-specific variant of Sept8 that was abundant in neurons and modified by palmitoylation, specifically at Cys469, Cys470, and Cys472. Sept8-204 palmitoylation was mediated by the palmitoyltransferase ZDHHC7 and was removed by the depalmitoylase PPT1. Palmitoylation of Sept8-204 bound to F-actin and induced cytoskeletal dynamics to promote the outgrowth of filopodia in N2a cells and the arborization of neurites in hippocampal neurons. In contrast, a Sept8-204 variant that could not be palmitoylated because of mutation of all three Cys residues (Sept8-204-3CA) lost its ability to bind F-actin, and expression of this mutant did not promote morphological changes. Genetic deletion of Sept8, Sept8-204, or Zdhhc7 caused deficits in learning and memory and promoted anxiety-like behaviors in mice. Our findings provide greater insight into the regulation of Sept8-204 by palmitoylation and its role in neuronal morphology and function in relation to cognition.


Subject(s)
Actins , Septins , Animals , Humans , Mice , Actins/genetics , Anxiety/genetics , Neurons/physiology , Pseudopodia/genetics , Septins/genetics , Septins/metabolism , Learning
18.
Genes Brain Behav ; 22(6): e12863, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37575018

ABSTRACT

An environmental risk factor for schizophrenia (SZ) is maternal infection, which exerts longstanding effects on the neurodevelopment of offspring. Accumulating evidence suggests that synaptic disturbances may contribute to the pathology of the disease, but the underlying molecular mechanisms remain poorly understood. Erythropoietin-producing hepatocellular B (EphB) receptor signaling plays an important role in synaptic plasticity by regulating the formation and maturation of dendritic spines and regulating excitatory neurotransmission. We examined whether EphB receptors and downstream associated proteins are susceptible to environmental risk factors implicated in the etiology of synaptic disturbances in SZ. Using an established rodent model, which closely imitates the characteristics of SZ, we observed the behavioral performance and synaptic structure of male offspring in adolescence and early adulthood. We then analyzed the expression of EphB receptors and associated proteins in the prefrontal cortex and hippocampus. Maternal immune activation offspring showed significantly progressive cognitive impairment and pre-pulse inhibition deficits together with an increase in the expression of EphB2 receptors and NMDA receptor subunits. We also found changes in EphB receptor downstream signaling, in particular, a decrease in phospho-cofilin levels which may explain the reduced dendritic spine density. Besides, we found that the AMPA glutamate, another glutamate ionic receptor associated with cofilin, decreased significantly in maternal immune activation offspring. Thus, alterations in EphB signaling induced by immune activation during pregnancy may underlie disruptions in synaptic plasticity and function in the prefrontal cortex and hippocampus associated with behavioral and cognitive impairment. These findings may provide insight into the mechanisms underlying SZ.


Subject(s)
Carcinoma, Hepatocellular , Erythropoietin , Liver Neoplasms , Female , Pregnancy , Rats , Animals , Male , Neurons/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Receptors, Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Prefrontal Cortex/metabolism , Hippocampus/metabolism , Glutamic Acid/metabolism , Erythropoietin/metabolism , Erythropoietin/pharmacology , Receptors, Eph Family/metabolism , Actin Depolymerizing Factors/metabolism , Actin Depolymerizing Factors/pharmacology , Neuronal Plasticity
19.
Mil Med Res ; 10(1): 24, 2023 06 02.
Article in English | MEDLINE | ID: mdl-37269009

ABSTRACT

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R2 for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).


Subject(s)
Antipsychotic Agents , Schizophrenia , Humans , Antipsychotic Agents/adverse effects , Schizophrenia/drug therapy , Schizophrenia/genetics , Schizophrenia/chemically induced , Olanzapine/pharmacology , Olanzapine/therapeutic use , Risperidone/adverse effects , Aripiprazole/pharmacology , Aripiprazole/therapeutic use , Precision Medicine , Multiomics , Benzodiazepines/adverse effects , Randomized Controlled Trials as Topic , Phospholipases/therapeutic use
20.
Neuroimage Clin ; 39: 103451, 2023.
Article in English | MEDLINE | ID: mdl-37315484

ABSTRACT

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) patients display significant structural brain abnormalities; nevertheless, the genetic mechanisms regulating cortical anatomical variations and their correlation with the disease phenotype are still ambiguous. STUDY DESIGN: We characterized anatomical variation using a surface-based method derived from structural magnetic resonance imaging of patients with SZ and age- and sex-matched healthy controls (HCs). Partial least-squares regression was performed across cortex regions between anatomical variation and average transcriptional profiles of SZ risk genes and all qualified genes from the Allen Human Brain Atlas. The morphological features of each brain region were correlated to symptomology variables in patients with SZ using partial correlation analysis. STUDY RESULTS: A total of 203 SZ and 201 HCs were included in the final analysis. We observed significant variation of 55 regions of cortical thickness, 23 regions of volume, 7 regions of area, and 55 regions of local gyrification index (LGI) between SZ and HC groups. Expression profiles of 4 SZ risk genes and 96 genes from all qualified genes showed a correlation to anatomical variability, however, after multiple comparisons, the correlations were no longer significant. LGI variability in multiple frontal subregions was associated with specific symptoms of SZ, whereas cognitive function involving attention/vigilance was linked to LGI variability across nine brain regions. CONCLUSIONS: Cortical anatomical variation of patients with schizophrenia is associated with gene transcriptome profiles as well as clinical phenotypes.


Subject(s)
Schizophrenia , Transcriptome , Humans , Transcriptome/genetics , Schizophrenia/diagnostic imaging , Schizophrenia/genetics , Schizophrenia/complications , Brain/diagnostic imaging , Magnetic Resonance Imaging , Phenotype , Cerebral Cortex/diagnostic imaging
SELECTION OF CITATIONS
SEARCH DETAIL
...