Li Tian

We aimed to identify cord blood metabolic measures associated with childhood-onset neurodevelopmental disorders (NDDs) and to examine whether they improve prediction beyond known early-life risk factors. In a prospective study of 858 children followed to a median age of 14.1 years (IQR 13.7–14.8), cord blood levels of 110 metabolic measures were assessed at birth and NDD diagnoses obtained from nationwide register. We identified 12 cord blood metabolic measures together explaining 5.0% of variance in any NDD, seven related to HDL synthesis, concentration and composition, one to concentration of lipoprotein particles, two to fatty acids and two to amino acids; their levels were 0.26–0.36(95%CI: −0.55, −0.06) standard deviations lower in the children who were later diagnosed with any NDD compared to the children with no mental disorders (p-value for overall model including all 12 metabolic measures <0.0001). They were also associated with early-life risk factors of NDDs, and improved the prediction of any NDD over a model that included only sociodemographic, prenatal and birth-related early-life risk factors(AUC = 0.74,95% CI 0.69–0.79; R2 = 16.6%; p < 0.0001 vs. AUC 0.71,95% CI, 0.66–0.76; R2 = 12.2%; p < 0.0001; Likelihood Ratio Test [LRT] p = 0.04). The improvement was more modest when the model additionally included maternal polygenic risk scores for ADHD and ASD (AUC = 0.75,95% CI 0.70–0.80; R2 = 18.3%; p < 0.0001 vs. AUC 0.72,95% CI, 0.67–0.78; R2 = 13.9%; p < 0.0001; LRT p = 0.08). Cord blood metabolic measures predicted NDDs diagnosed from birth through adolescence and improved prediction beyond early-life risk factors, with smaller incremental value when maternal PRSs for ADHD and ASD were included.

Norepinephrine (NE) in the peripheral nervous system plays crucial roles in regulating peripheral organs in health and disease. However, the spatiotemporal dynamics of sympathetic NE release and its underlying mechanisms remain poorly characterized due to technical challenges. Here, we developed and validated a Slice ElectroChemistry (SEC) method to record sympathetic NE release in heart slices with combined super-resolution and high sensitivity at 1 μm × 1 ms × 1 nM as in patch-clamp recordings. By using the SEC method, we revealed the increased NE release, impaired NE reuptake, increased releasable NE-vesicle pool, and impaired vesicle recycling of sympathetic nerves in the heart of transverse aortic constriction-induced heart failure (HF) mouse model, and defined the increased expression of Cav2.2 calcium channel as a central mechanism mediating the facilitation of NE release and thus the pathogenesis of HF, clarifying a longstanding puzzle about the kinetic changes of cardiac sympathetic NE release in HF. Beyond the heart, SEC enables NE release recording in other peripheral organs and human tissues, providing a robust toolset to investigate sympathetic NE dynamics across diverse pathophysiological conditions.

Background and Hypothesis: Accurate prediction of treatment response is essential for optimizing therapeutic strategies in patients with schizophrenia. Compared to neuroimaging or genetic biomarkers, clinical symptom patterns have received relatively little attention as predictors of treatment outcome. This study aimed to address this gap by comprehensively analyzing early symptom trajectories to predict long-term treatment outcomes. Study Design: A cohort of 387 inpatients with schizophrenia during acute episodes was followed for 8 weeks of standardized antipsychotic treatment. Clinical symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS) at baseline, week 2, and week 8. Using network analysis and machine learning model, we evaluated symptom patterns associated with treatment outcome and the predictive value of early clinical symptom trajectories. Study Results: (1) Effective treatment responders (ETR) and poor treatment responders (PTR) exhibited distinct clinical symptom profiles at baseline and early treatment response. (2) At week 2, ETR patients showed a denser PANSS change network compared to PTR, indicating more coordinated symptom changes. (3) Early symptom change was significantly correlated with 8-week treatment outcome. (4) Although the absence of early treatment response had limited predictive value, a machine learning model based on early %PANSS change achieved 76% balanced accuracy, with changes in the negative domain emerging as key predictors. Conclusions: These findings highlight the distinctive symptom profiles associated with different treatment outcomes and underscore the importance of early symptom patterns in predicting 8-week responses in patients with acute schizophrenia.

Background: Parental genetics matters for children’s behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear.Methods: We studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results.Findings: We observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all pFDR<0·001; for school-aged externalising difficulties, PGSc-ADHD: β=0·121 [95% CI 0·091 to 0·151], pFDR<0·0001; PGSc-EA: β=-0·095 [95% CI -0·127 to -0·063], pFDR<0·0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all pFDR<0·05; for school-aged internalising difficulties, PGSm-MDD: β=0·049 [95% CI 0·017 to 0·081], pFDR=0·016; PGSm-PC1: β=0·056 [95% CI 0·022 to 0·091], pFDR=0·011). No statistically significant effects from paternal PGSs were identified.Interpretation: In this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties.

Immunopsychiatric field has rapidly accumulated evidence demonstrating the involvement of both innate and adaptive immune components in psychotic disorders such as schizophrenia. Nevertheless, researchers are facing dilemmas of discrepant findings of immunophenotypes both outside and inside the brains of psychotic patients, as discovered by recent meta-analyses. These discrepancies make interpretations and interrogations on their roles in psychosis remain vague and even controversial, regarding whether certain immune cells are more activated or less so, and whether they are causal or consequential, or beneficial or harmful for psychosis. Addressing these issues for psychosis is not at all trivial, as immune cells either outside or inside the brain are an enormously heterogeneous and plastic cell population, falling into a vast range of lineages and subgroups, and functioning differently and malleably in context-dependent manners. This review aims to overview the currently known immunophenotypes of patients with psychosis, and provocatively suggest the premature immune “burnout” or inflamm-aging initiated since organ development as a potential primary mechanism behind these immunophenotypes and the pathogenesis of psychotic disorders.

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.

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 (β = −0.442, 95% CI: −1.326 ~ −0.087).Conclusion: Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

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.

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 (FDRPLXNB2 level were both negatively correlated with stress perception (pPLXNB2 expression (β=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 (ppppPLXNB2 regulates amygdala-dependent stress responses.

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.