Immunosenescence-related T cell phenotypes and white matter in schizophrenia patients with tardive dyskinesia.

Schizophrenia patients with tardive dyskinesia (TD) are associated with accelerated biological aging, immunological dysfunction, and premature morbidity and mortality. Older individuals are particularly vulnerable to TD development. As a characteristic of immunosenescence, alterations in the relative proportions of naïve or memory T cell subpopulations may be negatively or positively associated with brain structure abnormalities; however, whether these changes are correlated with TD remains unclear. In this study, we investigated correlations between distributions of T cell phenotypes and brain structure abnormalities (especially white matter) in schizophrenia patients with (TD) and without (NTD) TD (n = 50 and 58, respectively) relative to healthy controls (HC, n = 41). Immune markers, including naïve (CD45RA+), memory (CD45RO+), and apoptotic (CD95+) CD4+ and CD8+ T cells, were examined by flow cytometry, as were the intracellular levels of cytokines (interferon (IFN)-γ, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α) in CD8 + CD45RA + CD95+ and CD8 + CD45RO + CD95+ T cells. MRI was employed to evaluate the fractional anisotropy (FA) of white matter tracts and subcortical volumes, following published routines. The percentage of CD8 + CD45RO + CD95+ T cells was higher in TD compared with NTD and HC groups and correlated with the choroid plexus volume in TD group. The intracellular level of IFN-γ in CD8 + CD45RO + CD95+ T cells, the FA of the fornix/stria terminalis, and the pallidum volume were correlated with orofacial TD, whereas the FAs of the inferior fronto-occipital fasciculus, cingulum, and superior longitudinal fasciculus were correlated with limb-truncal TD. These findings provide preliminary evidence that the association between immunosenescence-related T cell subpopulations and brain structure may underline the pathological process of TD.

Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders.

Background: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD). Methods: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale (YMRS) were used to evaluate depressive and manic symptoms at baseline and after 8 weeks of antidepressants, mood stabilizers, some also received antipsychotic medication. Results: The levels of tryptophan (TRP) and kynurenic acid (KYNA) were significantly lower and the ratios of tryptophan/kynurenine (TRP/KYN), 5-hydroxytryptamine/tryptophan (5-HT/TRP), quinolinic acid/kynurenic acid (QUIN/KYNA) were higher in BD-M, BD-D, MDD vs. HC. The levels of QUIN and the ratios of QUIN/KYNA were higher in BD-M than in BD-D, MDD, and HCs. The 5-hydroxyindoleacetic acid (5-HIAA) levels of patients with MDD were significantly higher than those in BD-M and BD-D. Binary logistic regression analysis showed the lower peripheral KYNA, the higher the QUIN level, and the higher the risk of BD-M; the lower peripheral KYNA and the higher KYN/TRP and 5-HT/TRP, the higher the risk of BD-D; and the lower the peripheral KYNA level and the higher the KYN/TRP and 5-HT/TRP, the higher the risk of MDD. Correlation analysis, showing a significant association between tryptophan metabolites and improvement of clinical symptoms, especially depression symptoms. Conclusions: Patients with affective disorders had abnormal tryptophan metabolism, which involved in 5-HT and kynurenine pathway (KP) sub-pathway. Tryptophan metabolites might be potential biomarkers for affective disorders and some metabolites have been associated with remission of depressive symptoms.

Immune-Inflammatory Response And Compensatory Immune-Regulatory Reflex Systems And White Matter Integrity in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Low-grade neural and peripheral inflammation are among the proposed pathophysiological mechanisms of schizophrenia. White matter impairment is one of the more consistent findings in schizophrenia but the underlying mechanism remains obscure. Many cerebral white matter components are sensitive to neuroinflammatory conditions that can result in demyelination, altered oligodendrocyte differentiation, and other changes. We tested the hypothesis that altered immune-inflammatory response system (IRS) and compensatory immune-regulatory reflex system (IRS/CIRS) dynamics are associated with reduced white matter integrity in patients with schizophrenia. STUDY DESIGN: Patients with schizophrenia (SCZ, 70M/50F, age = 40.76 ±â€…13.10) and healthy controls (HCs, 38M/27F, age = 37.48 ±â€…12.31) underwent neuroimaging and plasma collection. A panel of cytokines were assessed using enzyme-linked immunosorbent assay. White matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging using a 3-T Prisma MRI scanner. The cytokines were used to generate 3 composite scores: IRS, CIRS, and IRS/CIRS ratio. STUDY RESULTS: The IRS/CIRS ratio in SCZ was significantly higher than that in HCs (P = .009). SCZ had a significantly lower whole-brain white matter average FA (P < .001), and genu of corpus callosum (GCC) was the most affected white matter tract and its FA was significantly associated with IRS/CIRS (r = 0.29, P = .002). FA of GCC was negatively associated with negative symptom scores in SCZ (r = -0.23, P = .016). There was no mediation effect taking FA of GCC as mediator, for that IRS/CIRS was not associated with negative symptom score significantly (P = .217) in SCZ. CONCLUSIONS: Elevated IRS/CIRS might partly account for the severity of negative symptoms through targeting the integrity of GCC.

Role of the immune-kynurenine pathway in treatment-resistant schizophrenia.

BACKGROUND: The immune-inflammatory response system (IRS) and kynurenine pathway (KP) have been implicated in the pathophysiology of schizophrenia. Studies have shown inflammation-related effects on KP metabolism in patients with schizophrenia. This study investigated the relationship between KP metabolites, IRS, and the compensatory immune-regulatory reflex system (CIRS) in patients with treatment-resistant schizophrenia (TRS). METHODS: Patients with (n = 53) and without TRS (n = 47), and healthy controls (HCs, n = 49) were enrolled. We quantified plasma levels of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-2, IL-6, soluble(s)IL-6 receptor, IL-8, IL-12, IL-17, IL-18, interferon-γ, and tumor necrosis factor[TNF]-α) and anti-inflammatory cytokines (IL-1 receptor antagonist, IL-4, IL-10, tumor growth factor [TGF]-ß1, TGF-ß2, soluble (s) IL-2 receptor subunit α, sIL-2 receptor subunit ß, and sTNF-α receptor 1) and calculated the IRS/CIRS ratio. We also tested serum metabolites of the KP, including kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN), along with the QUIN/KYNA ratio. RESULTS: Patients with TRS had significantly higher IRS/CIRS ratio than non-TRS patients (p = 0.002) and HCs (p = 0.007), and significantly lower KYN (p = 0.001) and KYNA (p = 0.01) levels than HCs. Binary logistic regression analysis revealed that a younger age at illness onset (odds ratio [OR] = 0.91, p = 0.02) and a higher IRS/CIRS ratio (OR = 1.22; p = 0.007) were risk factors for patients with TRS. After further adjusted for age of onset, the QUIN/KYNA ratio (ß = 0.97; p = 0.02) significantly moderated the relationship between IRS/CIRS and TRS, showing that in the higher QUIN/KYNA condition, higher IRS/CIRS ratio were significantly and more likely to be associated with patients with TRS (ß = 0.12, z = 3.19, p = 0.001), whereas in the low QUIN/KYNA condition, the association between IRS/CIRS ratio and TRS was weak and insignificant. CONCLUSIONS: The peripheral immune response was imbalanced in TRS and was preferentially directed towards the IRS compared to patients without TRS and healthy controls, which is likely to play a role in neurotoxicity. Additionally, peripheral KP activation was also imbalanced, as evidenced by significantly reduced KYN and KYNA levels in patients with TRS compared to healthy controls, but none of KP metabolisms were significantly difference in non-TRS patients compared to healthy controls. QUIN/KYNA ratio involving to the degree of activation of NMDA receptors, indicated the neurotoxic level of the KP activation. The interaction between IRS/CIRS and QUIN/KYNA ratio was significant in predicting TRS, and our findings suggest a potential role for the immune-kynurenine pathway in TRS pathogenesis.

Correlation of Immune-Inflammatory Response System (IRS)/Compensatory Immune-Regulatory Reflex System (CIRS) with White Matter Integrity in First-Episode Patients with Schizophrenia.

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

Replenished microglia partially rescue schizophrenia-related stress response.

Background: Microglia play an important role in the maintenance of brain and behavioral homeostasis. The protective effect of microglial replenishment was reported in neurological diseases, but whether microglial therapy would benefit psychiatric disorders such as schizophrenia has been unclear. As schizophrenia is a stress-vulnerable disorder and psychosocial stress promotes inflammation and microglial activation, we aim to understand how microglial replenishment works in stress-associated schizophrenia. Methods: We used a CSF1R-mediated pharmacological approach to study repopulated microglia (repMg) in a cohort of mice (n = 10/group) undergoing chronic unpredictable stress (CUS). We further studied a cohort of first-episode schizophrenia (FES, n = 74) patients who had higher perceived stress scores (PSS) than healthy controls (HCs, n = 68). Results: Reborn microglia attenuated CUS-induced learned hopelessness and social withdrawal but not anxiety in mice. Compared to control, CUS- or repMg-induced differentially expressed genes (DEGs) in the prefrontal cortex regulated nervous system development and axonal guidance. CUS also caused microglial hyper-ramification and increased engulfment of synaptophysin and vesicular glutamate transporter-2 by microglia and astrocytes, which were recovered in CUS + repMg (all p < 0.05). Moreover, FES patients had smaller hippocampal fimbria than HCs (p < 1e-7), which were negatively associated with PSS (r = -0.397, p = 0.003). Blood DEGs involved in immune system development were also associated with PSS and the right fimbria more prominently in FES patients than HCs (Zr, p < 0.0001). The KCNQ1 was a partial mediator between PSS and fimbria size (ß = -0.442, 95% CI: -1.326 ~ -0.087). Conclusion: Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages.

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility. METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology. RESULTS: FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05). CONCLUSION: Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

Inflammatory disequilibrium and lateral ventricular enlargement in treatment-resistant schizophrenia.

Treatment-resistant schizophrenia (TRS) patient respond poorly to antipsychotics. Inflammatory imbalance involving pro- and anti-inflammatory cytokines may play an important role in the mechanism of antipsychotic-medication response. This study aimed to investigate immune imbalance and how the latter relates to clinical manifestations in patients with TRS. The level of net inflammation was estimated by evaluating the immune-inflammatory response system and compensatory immune-regulatory reflex system (IRS/CIRS) in 52 patients with TRS, 47 with non-TRS, and 56 sex and age matched healthy controls. The immune biomarkers mainly included macrophagic M1, T helper, Th-1, Th-2, Th-17, and T regulatory cytokines and receptors. Plasma cytokine levels were measured using enzyme-linked immunosorbent assay. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Subcortical volumes were quantified using a 3-T Prisma Magnetic Resonance Imaging scanner. The results showed that (1) patients with TRS were characterized by activated pro-inflammatory cytokines and relatively insufficient anti-inflammatory cytokines, with an elevated IRS/CIRS ratio indicating a new homeostatic immune setpoint; (2) IRS/CIRS ratio was positively correlated with larger lateral ventricle volume and higher PANSS score in patients with TRS. Our findings highlighted the inflammatory disequilibrium as a potential pathophysiological process of TRS.

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.

Stress is a trigger for the development of psychiatric disorders. However, how stress trait differs in schizophrenia patients is still unclear. Stress also induces and exacerbates immune activation in psychiatric disorders. Plexins (Plxn) and its ligands semaphorins (Sema) are important cellular receptors with plural functions in both the brain and the immune system. Recently, the role of Plxn/Sema in regulation of neuroinflammation was also noticed. Here, when investigating immune mechanisms underlying stress susceptibility in schizophrenia, we discovered the role of Plxnb2 in stress response. Patients of first-episode schizophrenia (FES) with high stress (FES-hs, n=51) and low stress (FES-ls, n=50) perception and healthy controls (HCs) (n=49) were first recruited for neuroimaging and blood bulk RNA sequencing (RNA-seq). A mouse model of chronic unpredictable stress (CUS) and intra-amygdaloid functional blocking of Plxnb2 were further explored to depict target gene functions. Compared to HCs, FES-hs patients had bigger caudate and thalamus (FDR=0.02&0.001, respectively) whereas FES-ls patients had smaller amygdala (FDR=0.002). Blood RNA-seq showed differentially expressed PLXNB2 and its ligands among patient groups and HCs (FDR<0.05~0.01). Amygdaloid size and PLXNB2 level were both negatively correlated with stress perception (p<0.01&0.05, respectively), which fully mediated the amygdaloid positive association with PLXNB2 expression (ß=0.9318, 95% CI: 0.058~1.886) in FES-hs patients. In mice, Plxnb2 was enriched in astrocytes and microglia and CUS reduced its expression in astrocytes (p<0.05). Inhibition of amygdaloid Plxnb2 by its functional blocking monoclonal antibody (mAb)-102 induced mice anxiety (p<0.05), amygdaloid enlargement (p<0.05), and microglial ramification (p<0.001) compared to saline. These data suggest that PLXNB2 regulates amygdala-dependent stress responses.

Alterations in innate immune defense distinguish first-episode schizophrenia patients from healthy controls.

Innate immune components involved in host defense have been implicated in schizophrenia (SCZ). However, studies exploring their clinical utility in SCZ diagnosis are limited. The main purpose of this study was to evaluate whether circulating endotoxin, high mobility group box 1 protein (HMGB1) and complement component 4 (C4) could act as peripheral biomarkers to distinguish first-episode schizophrenia (FES, n = 42) patients from healthy controls (HCs, n = 35) in associations with psychopathological symptoms and cognitive dysfunctions. Also, their changes after 8-week antipsychotic treatment were investigated. The Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), and MATRICS Consensus Cognitive Battery (MCCB) were administered. Receiver operating characteristic (ROC) curves were conducted to evaluate the diagnostic effectiveness of the three biological indicators. Compared to HCs, levels of endotoxin, HMGB1, and C4 were remarkably increased in FES patients after controlling for age, gender, body mass index (BMI) and education years, and the combination of the three biomarkers demonstrated desirable diagnostic performance (AUC = 0.933). Moreover, the endotoxin level was positively correlated with the severity of auditory hallucinations. After 8 weeks of treatment, HMGB1 was decreased significantly in patients but still higher than that in HCs, whereas endotoxin and C4 did not change statistically. The baseline levels of endotoxin, HMGB1, and C4, as well as their changes were not associated with changes in any PANSS subscale score and total score. Our preliminary results suggest that a composite peripheral biomarker of endotoxin, HMGB1, and C4 may have accessory diagnostic value to distinguish SCZ patients from HCs. Additionally, endotoxin might be implicated in the pathogenesis of auditory hallucinations.

The relationship between TLR4/NF-κB/IL-1ß signaling, cognitive impairment, and white-matter integrity in patients with stable chronic schizophrenia.

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

Serum hyperhomocysteine and cognitive impairment in first-episode patients with schizophrenia: Moderated by brain cortical thickness.

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

Kynurenine metabolism and metabolic syndrome in patients with schizophrenia.

Accumulating evidence indicates that a dysregulated kynurenine (KYN) pathway (KP) metabolism may play an important role in the pathogenesis of both schizophrenia and metabolic syndrome (MS). However, the underlying mechanisms remain poorly understood. Here, we aimed to evaluate the potential roles of KP in the pathogenesis of MS in schizophrenia. A total of 160 schizophrenia patients and 70 healthy controls were enrolled in this study. KP metabolites were quantified, and MS scores were calculated, for comparisons between patients and controls. Associations among the indices were explored in both groups. Multiple linear regression analyses were performed to investigate the effects of KP metabolites on MS factors. We observed a significantly higher MS score, lower levels of all KP metabolites, and higher nicotinamide adenine dinucleotide (NAD+)/quinolinic acid (QUNA) in patients than in controls (all p < 0.01). Partial correlation analyses revealed that, in the patient group, QUNA and QUNA/KYN correlated positively with MS score (r = 0.24 and 0.27, respectively, both p < 0.025), and NAD+/QUNA correlated negatively with MS score (r = -0.25, p = 0.002). Results of multiple regression analyses showed significant QUNA × group interactions in the model representing QUNA effects on MS score (ß = 0.25) and a significant QUNA/KYN × group interaction in the model representing QUNA/KYN effects on MS score (ß = 0.23) (both p < 0.001). Among all factors contributing to MS in schizophrenia, an interactive effect of schizophrenia itself and dysregulated KP plays a contributory role. Conceivably, modulation of the KP could theoretically lead to treating schizophrenia and MS simultaneously.

Effects of microRNA-181b-5p on cognitive deficits in first-episode patients with schizophrenia: Mediated by BCL-2.

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

Allostatic Load Effects on Cortical and Cognitive Deficits in Essentially Normotensive, Normoweight Patients with Schizophrenia.

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

Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population.

Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.