Translational Psychiatry最新文献

Depression and dementia commonly co-occur, yet little is known about depression trajectories across dementia stages. We aimed to map depression occurrence before, during, and after dementia diagnosis, and to identify factors associated with depression among individuals with dementia. This study included 10,051 participants from the Swedish Twin Registry. Participants with incident dementia (n = 2677) were matched with up to 3 controls (n = 7374) by birth year and sex. Depression and dementia diagnoses and their dates were ascertained based on medical records from the National Patient Registry. Conditional Poisson regression estimated incidence rate ratios for depression, while generalized estimating equations examined odds ratios for factors associated with depression. Compared with controls, depression risk among participants with dementia began to increase 6 years pre-diagnosis (incidence rate ratio [95% confidence interval] 2.32 [1.24-4.35]) and peaked during the year of dementia diagnosis (10.38 [7.33-14.69]). Depression risk remained elevated but gradually declined over the following 4 years (3.10 [1.67-5.77]). Female sex (odds ratio 2.21 [1.63-2.99]), smoking (1.58 [1.20-2.08]), heavy drinking (1.88 [1.10-3.21]), and stroke (1.94 [1.31-2.88]) were associated with higher odds of depression before dementia diagnosis, whereas being single (1.71 [1.10-2.37]) and having a history of cancer (1.35 [1.05-1.79]) were associated with post-diagnosis depression. Overall, these findings indicate that depression risk rises before, peaks at, and remains elevated after dementia diagnosis, with specific demographic (sex, marital status) and health-related factors (smoking, alcohol use, stroke, cancer) contributing to its occurrence among individuals with dementia.

Nonsuicidal self-injury (NSSI) in youth is clinically heterogeneous. We aimed to identify distinct psychopathology-based profiles among children and adolescents reporting NSSI and their longitudinal correlates. Participants (N = 1 345) were drawn from the Brazilian High-Risk Cohort Study, which conducted extensive phenotypic assessments at baseline (ages 6-14 years) and across two follow-up waves (ages 9-18 and 13-23 years). First, we applied unsupervised machine-learning algorithms (Self-Organizing Maps and k-means clustering) to identify distinct psychopathology-based profiles among youth reporting NSSI at the second follow-up. We then employed three models to identify longitudinal predictors of these profiles: logistic regression, elastic net, and random forest. Analyses revealed two distinct profiles of youth reporting NSSI, characterized by high and low psychopathology. The high psychopathology profile (n = 117) was associated with factors identifiable earlier in life and characterized by persistent psychiatric symptoms and significant social adversity throughout development (e.g., family problems and bullying). The low psychopathology profile (n = 127) was marked by lower overall psychopathology and experienced mental health problems only later in development, with less severe challenges over time, such as school suspension and milder depressive symptoms. While the logistic regression did not provide overall significant performance, the elastic net (AUC = 0.72 95% CI 0.65-0.77) and random forest (AUC = 0.73 95% CI 0.67-0.78) did. The present study identified two distinct psychopathology-based profiles among youth reporting NSSI and their longitudinal correlates, using machine learning approaches. Early identification of youth in higher-risk profiles can inform early intervention strategies.

Schizophrenia is a severe psychiatric disorder that affects approximately 1% of the population. Despite the availability of antipsychotic therapies, about 30% of patients develop treatment-resistant schizophrenia (TRS), defined by a lack of response to at least two different antipsychotic trials. Although several genetic and environmental factors have been proposed to explain treatment resistance, metabolomic studies investigating circulating metabolites in TRS remain limited. In this pilot cross-sectional study, we conducted untargeted ¹H NMR-based metabolomics to profile serum metabolites in TRS versus non-TRS patients. Notably, multivariate analysis revealed distinct serum metabolome profiles between the two groups. Additionally, Variable Importance in Projection (VIP) analysis and robust volcano plots showed significant differences between TRS versus non-TRS patients in metabolites involved in lipid and amino acid metabolism. Specifically, serine and glycine emerged as key discriminating molecules, prompting a complementary targeted HPLC analysis in the same serum samples. Although no significant group differences were observed in L-serine, D-serine, the D-serine/total serine ratio, or glycine levels, we found a positive correlation between D-serine levels and cognitive performance, particularly in the area of executive function, across the entire patient cohort. Additionally, a significant correlation between glycine and disorganization symptoms was found selectively in TRS patients. In conclusion, our study offers new insights into potential biomarkers for TRS, highlighting serine-glycine pathway as a possible crossroad between systemic dysmetabolism, NMDA receptor dysfunction, and cognitive impairment in TRS.

The neuronal ceroid lipofuscinosis family of lysosomal storage diseases, also called CLN1 disease, is characterized by the deficiency of palmitoyl-protein thioesterase 1 (PPT1). In this study, we investigated the impact of PPT1 deficiency on hippocampal GABAergic interneurons (INs) and associated neural network oscillations in a PPT1-KI (CLN1 c.451 C > T (p.R151X)) mouse model. Using a combination of in vivo electrophysiology, immunostaining, and fiber photometry, we observed that PPT1 deficiency led to the activation of caspase 3 in parvalbumin-positive (PV⁺) INs, an increased activity of pyramidal neurons and theta/gamma oscillation power, and the disruption of theta-gamma cross-frequency coupling (CFC) in the early stage of the CLN1 disease model. In the late stage of the CLN1 disease model, we observed the reduced neuronal activity, extensive neuronal loss including PV⁺ INs, and the emergence of spontaneous epileptiform discharges and the pathological ripples. Treatment with diazepam partially restored oscillatory coupling and reduced seizure-like activities. Our research indicated that PPT1 deficiency leads to early selective impairment of PV⁺ INs, triggering overactivation of pyramidal neurons and network dysfunction, which consequently results in seizures and neurodegeneration. This research provides novel insights into the pathogenesis of CLN1 disease and potential therapeutic strategies for the intervention of CLN1 disease by improving the function of inhibitory INs via caspase inhibition.

Postpartum depression (PPD) is linked to neuroimmune dysregulation. Brexanolone, an intravenous formulation of the neurosteroid allopregnanolone and the first FDA-approved treatment for PPD, produces rapid and sustained antidepressant effects. However, its long-term mechanisms of action remain unclear. This study evaluated brexanolone's prolonged impact on two groups of biomarkers in whole blood: inflammatory mediators and growth/differentiation/neurotrophic factors. Whole blood was also maintained in culture (4 h) and subjected to lipopolysaccharide (LPS) stimulation of the TLR4 inflammatory pathway. Ten individuals with moderate-to-severe PPD received brexanolone and were assessed before, and at 6 h, ~7, and ~30 days post-infusion. BDNF significantly increased and remained elevated through 30 days, representing a sustained neurotrophic response. In contrast, inflammatory mediators CCL11, IL-6, TNF-α, and IL-18 showed rapid reductions by 6 h. TNF-α suppression lasted up to 7 days, while CCL11 and IL-6 remained suppressed through 30 days. These changes were associated with reductions in Hamilton Depression Rating Scale (HAM-D) scores over time. LPS-stimulated whole blood cultures revealed suppression of TLR4-induced CCL11, IL-1β, IL-6, IL-8, IL-18, TNF-α, HMGB1, and MIP-1β at 6 h. IL-8, IL-18, and TNF-α remained suppressed through 7 days, while IL-1β and CCL11 remained suppressed through 30 days, aligning with sustained HAM-D score improvements. Biomarker × time interactions suggested dynamic regulation of inflammatory and neurotrophic pathways. Given the small sample size, these findings should be interpreted as a pilot study, but they indicate that brexanolone promotes both rapid and sustained anti-inflammatory and neurotrophic effects supporting lasting symptom remission in PPD.

Cognitive deficits are a hallmark of Alzheimer's disease (AD), and effective treatments remain elusive. Transcranial alternating current stimulation (tACS), a non-invasive technique, has shown potential in improving cognitive function across various populations, but further research is needed to investigate its efficacy in AD. In a randomized, double-blind, sham-controlled pilot trial, 36 mild AD patients received active or sham theta-tACS (8 Hz, 1.6 mA, 20-min daily) during n-back task for two weeks, followed by a 10-week follow-up. Cognitive assessments and resting-state EEG were analyzed at baseline, after-treatment, and follow-up. The results showed that the active group demonstrated significant cognitive improvements after treatment (MMSE: t (15) =-3.273, p = 0.005, Cohen's d = 0.82), particularly in short-term memory (MMSE-recall: Z = -2.11, p = 0.035, r = 0.53), with maintained benefits after 10 weeks. In contrast, the sham group exhibited long-term cognitive decline (MMSE: t (4) = 3.586, p = 0.023, Cohen's d = -1.60). EEG analysis revealed reduced gamma power (t (23) = 2.689, p = 0.013, Cohen's d = 1.077) and theta connectivity in active group, particularly in the frontotemporal regions (F4/F7: t (23) = 2.467, p = 0.021, Cohen's d = 0.988; F4/T3: t (23) = 2.465, p = 0.022, Cohen's d = 0.987), which was correlated with cognitive improvements (R = -0.57, p = 0.043). In conclusion, tACS combining cognitive training may offer cognitive benefits in mild AD by modulating neural activity, though further studies are needed to clarify its mechanisms.

Social valence is the directional emotional significance affiliated with social experiences. Maladaptive social information processing has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in social valence processing, we employed behavioral tasks that associated conspecific identity recognition with either positive or negative valence, as well as tasks in which valence information originated from social targets. Male mice demonstrated identity recognition regardless of social valence. While male and female mice performed similarly in the positive social valence task, female mice did not show identity recognition following the negative social valence task. In vivo calcium imaging of the dorsal CA1 further revealed sex differences in negative social valence processing with reduced hippocampal representation of social information in female mice. Finally, enhancing dorsal CA1 neuronal activity by ampakine rescued identity recognition in female mice. These results suggest that sex differences in social valence processing may contribute to the heightened vulnerability to social stress-related mood disorders in women.

Cognitive deficits across multiple domains are prevalent in patients with schizophrenia (PWS), and metabolic syndrome (MetS) may significantly contribute to this impairment. To clarify the complex relationships between individual MetS components and multidimensional cognitive dysfunction in PWS, we conducted a multicenter study involving 727 clinically stable patients recruited from ten psychiatric hospitals. Cognitive function was assessed using the Chinese Brief Cognitive Test (C-BCT). We employed network analysis and structural equation modeling (SEM) to explore these associations, with machine learning techniques applied for further validation. The results revealed statistically significant differences in several cognitive domains between patients with and without dyslipidemia (DL). Patients with hypertension (HT) also exhibited overall poorer cognitive performance. Network analysis indicated meaningful distinctions between patients presenting two or more MetS components (MetS-2+) and those without, showing a sparser network configuration in the MetS-2+ group. Across both groups, the Symbol Coding task demonstrated the highest strength centrality. SEM indicated that metabolic indicators, specifically DL and HT, mediated the relationship between clinical symptoms and cognitive function. Furthermore, a transformer-based machine learning model performed effectively in predicting cognitive dimensions, supporting the predictive utility of MetS components for multidimensional cognitive outcomes. In summary, specific MetS components, particularly DL and HT, show intricate associations with cognitive function in stable-phase PWS. Our findings suggest that management of HT in this population may represent a potential pathway for cognitive enhancement and improved social functioning. Trial registration: MR-11-23-007343.

Oral cannabidiol (CBD) treatment has been suggested to alleviate severe symptoms of autism spectrum disorder (ASD). While many CBD preparations have been studied in clinical trials involving ASD, none has used purified CBD preparations or preparations approved by the U.S. Food and Drug Administration, nor have they focused on children with ASD with higher support needs. Previous studies have identified several candidate electrophysiological biomarkers of cognitive and behavioral disabilities in ASD, with emerging biomarkers including periodic (oscillatory) and aperiodic measures of neural activity. We analyzed electroencephalography (EEG) recordings from 24 boys with ASD and higher support needs (aged 7-14 years) from a prior double-blind, placebo-controlled, crossover Phase II Clinical Trial (NCT04517799) that investigated whether 8 weeks of daily CBD treatment (up to 20 mg/kg/day) improved severe behavioral problems, measured at baseline, post-CBD, post-placebo, and post-washout. Using linear mixed effect models, we found that aperiodic EEG measures varied with CBD metabolite levels in blood, as evidenced by a larger aperiodic offset across the scalp and a decreased aperiodic exponent across occipital electrodes. Furthermore, CBD metabolite levels in blood had a positive association with receptive vocabulary, nonverbal intelligence and visuomotor coordination. Our data suggest that this daily CBD preparation and administration schedule produced mixed effects, with some children showing improvements in cognitive and behavioral abilities while others demonstrated limited changes. Our findings support the inclusion of aperiodic EEG measures alongside traditional oscillatory EEG measures as candidate biomarkers for tracking the variable clinical impact of purified CBD treatment in children with ASD.