Translational Psychiatry最新文献

Social isolation (SI) is a common phenomenon in the modern world, especially during the coronavirus disease 2019 pandemic, and causes lasting cognitive impairments and mental disorders. However, it is still unclear how SI alters molecules in the brain and induces behavioural dysfunctions. Here, we report that SI impairs cognitive function and induces depressive-like behaviours in C57BL/6 J mice, in addition to impairing synaptic plasticity and increasing the levels of APP cleavage-related enzymes, thereby promoting Aβ production. Moreover, we show that in APP/PS1 transgenic mice, SI accelerates pathological changes and behavioural deficits. Interestingly, downregulation of the expression of the BACE1 attenuates SI-induced Aβ toxicity and synaptic dysfunction. Furthermore, early intervention with BACE1 shRNA blocks SI-induced cognitive impairments. Together, our data strongly suggest that SI-induced upregulation of BACE1 expression mediates Aβ toxicity and induces behavioural deficits. Down-regulation of BACE1 may be a promising strategy for preventing SI-induced cognitive impairments.

Social bonding, essential for health and survival in all social species, depends on mu-opioid signalling in non-human mammals. A growing neuroimaging and psychopharmacology literature also implicates mu-opioids in human social connectedness. To determine the role of mu-opioids for social connectedness in healthy humans, we conducted a preregistered (https://osf.io/x5wmq) multilevel random-effects meta-analysis of randomised double-blind placebo-controlled opioid antagonist studies. We included data from 8 publications and 2 unpublished projects, totalling 17 outcomes (N = 455) sourced from a final literature search in Web of Science, Scopus, PubMed and EMBASE on October 12, 2023, and through community contributions. All studies used naltrexone (25–100 mg) to block the mu-opioid system and measured social connectedness by self-report. Opioid antagonism slightly reduced feelings of social connectedness (Hedges’ g [95% CI) = −0.20] [−0.32, −0.07]. Results were highly consistent within and between studies (I² = 23%). However, there was some indication of bias in favour of larger effects among smaller studies (Egger’s test: B = −2.16, SE = 0.93, z = −2.33, p = 0.02), and publication bias analysis indicated that the effect of naltrexone might be overestimated. The results clearly demonstrate that intact mu-opioid signalling is not essential for experiencing social connectedness, as robust feelings of connectedness are evident even during full pharmacological mu-opioid blockade. Nevertheless, antagonism reduced measures of social connection, consistent with a modulatory role of mu-opioids for human social connectedness. The modest effect size relative to findings in non-human animals, could be related to differences in measurement (subjective human responses versus behavioural/motivation indices in animals), species specific neural mechanisms, or naltrexone effects on other opioid receptor subtypes. In sum, these results help explain how mu-opioid dysregulation and social disconnection can contribute to disability, and conversely—how social connection can buffer risk of ill health.

Background

Neurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear.

Methods

To explore their putative causalities, we conducted bidirectional two-sample Mendelian randomization (MR) using genetic variants associated with 317 human blood metabolites (n_max = 215,551), g-Factor (an integrated index of multiple neurocognitive tests with n_max = 332,050), and 10 different psychiatric disorders (n = 9,725 to 807,553) from the large-scale genome-wide association studies of European ancestry. Mediation analysis was used to assess the potential causal pathway among the candidate metabolite, neurocognitive trait and corresponding psychiatric disorder.

Results

MR evidence indicated that genetically predicted acetylornithine was positively associated with g-Factor (0.035 standard deviation units increase in g-Factor per one standard deviation increase in acetylornithine level; 95% confidence interval, 0.021 to 0.049; P = 1.15 × 10⁻⁶). Genetically predicted butyrylcarnitine was negatively associated with g-Factor (0.028 standard deviation units decrease in g-Factor per one standard deviation increase in genetically proxied butyrylcarnitine; 95% confidence interval, −0.041 to −0.015; P = 1.31 × 10⁻⁵). There was no evidence of associations between genetically proxied g-Factor and metabolites. Furthermore, the mediation analysis via two-step MR revealed that the causal pathway from acetylornithine to bipolar disorder was partly mediated by g-Factor, with a mediated proportion of 37.1%. Besides, g-Factor mediated the causal pathway from butyrylcarnitine to schizophrenia, with a mediated proportion of 37.5%. Other neurocognitive traits from different sources provided consistent findings.

Conclusion

Our results provide genetic evidence that acetylornithine protects against bipolar disorder through neurocognitive abilities, while butyrylcarnitine has an adverse effect on schizophrenia through neurocognition. These findings may provide insight into interventions at the metabolic level for risk of neurocognitive and related disorders.

Iron metabolism disorder has been identified as a contributor to the pathogenesis and progression of multiple cognitive dysfunction-related diseases, including postoperative delirium. However, the association between preoperative iron reserves and postoperative delirium risk remains elusive. This retrospective cohort study aimed to explore the impact of preoperative serum ferritin levels on the risk of postoperative delirium in elderly patients undergoing non-neurosurgical and non-cardiac procedures. Conducted at the Chinese PLA General Hospital between January 2014 and December 2021, the study finally included 12,841 patients aged 65 years and above. Preoperative serum ferritin levels were assessed within 30 days before surgery, and postoperative delirium occurrence within the first seven days after surgery was determined through medical chart review. The analyses revealed that both low and high levels of serum ferritin were associated with an increased risk of postoperative delirium. Patients in the lowest quintile of serum ferritin exhibited an 81% increased risk, while those in the highest quintile faced a 91% increased risk compared to those in the second quintile. Furthermore, mediation analyses indicated that the direct effect of preoperative serum ferritin on postoperative delirium contradicted its indirect effect mediated by hemoglobin levels. These findings suggest that maintaining serum ferritin within moderate range preoperatively could be beneficial for managing postoperative delirium risk among elderly patients.

Autism Spectrum Disorder (ASD) is a prevalent neurological condition with multiple co-occurring comorbidities that seriously affect mental health. Precisely diagnosis of ASD is crucial to intervention and rehabilitation. A single modality may not fully reflect the complex mechanisms underlying ASD, and combining multiple modalities enables a more comprehensive understanding. Here, we propose, DeepASD, an end-to-end trainable regularized graph learning method for ASD prediction, which incorporates heterogeneous multimodal data and latent inter-patient relationships to better understand the pathogenesis of ASD. DeepASD first learns cross-modal feature representations through a multimodal adversarial-regularized encoder, and then constructs adaptive patient similarity networks by leveraging the representations of each modality. DeepASD exploits inter-patient relationships to boost the ASD diagnosis that is implemented by a classifier compositing of graph neural networks. We apply DeepASD to the benchmarking Autism Brain Imaging Data Exchange (ABIDE) data with four modalities. Experimental results show that the proposed DeepASD outperforms eight state-of-the-art baselines on the benchmarking ABIDE data, showing an improvement of 13.25% in accuracy, 7.69% in AUC-ROC, and 17.10% in specificity. DeepASD holds promise for a more comprehensive insight of the complex mechanisms of ASD, leading to improved diagnosis performance.

Insomnia is highly comorbid in patients with psychiatric disorders, including depression, bipolar disorder, and substance use disorders, and should be treated as an independent condition. Dual orexin receptor antagonists (DORAs) have been investigated as a treatment for chronic insomnia. The objective of this systematic review was to examine evidence for two DORAs, lemborexant and suvorexant, as treatments for insomnia comorbid with a psychiatric disorder. We searched PubMed, Cochrane, and Embase from their inception until January and April 2023, and included studies examining suvorexant and lemborexant for treating insomnia comorbid with psychiatric disorders. We also manually searched clinical trial registries (https://clinicaltrials.gov and https://www.umin.ac.jp/ctr). Randomized clinical trials and observational/cohort studies were included. We identified 18 studies from PubMed, Cochrane, and Embase and three studies from clinicaltrials.gov and UMIN. Of the 21 reports, four were completed/terminated randomized clinical trials, eight were ongoing clinical trials, and nine were observational studies. We identified evidence for switching from benzodiazepine receptor agonists to a DORA, or using a DORA as add-on therapy and, therefore, discuss this topic as well. Two studies examined switching to or adding on a DORA in patients being treated with a benzodiazepine receptor agonist. DORAs may be as effective and safe for treating psychiatric comorbid insomnia (for most psychiatric conditions) as they are for treating primary insomnia. However, the evidence is limited to a few small studies. Further investigation of DORAs for the treatment of comorbid insomnia in those with coexisting psychiatric conditions is warranted.

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer’s disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep–wake cycle. The study population comprised people living with mild Alzheimer’s disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aβ40), amyloid-beta 42 (Aβ42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aβ40, Aβ42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-β-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

Observational and genetic studies have reported the relationship between dyslexia and Alzheimer’s disease (AD). Until now, the causal effect of dyslexia on AD risk has remained unclear. We conducted a two-sample univariable Mendelian randomization (MR) analysis to determine the causal association between dyslexia and the risk of AD, vascular dementia (VD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) and its four subtypes. First, we selected 42 dyslexia genetic variants from a large-scale genome-wide association studies (GWAS) dataset and extracted their corresponding GWAS summary statistics from AD, VD, LBD, and FTD. Second, we selected four MR methods, including inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. Heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analysis were then used to evaluate the reliability of all causal estimates. We also conducted multivariable MR (MVMR) and mediation analysis to assess the potential mediating role of cognitive performance (CP) or educational achievement (EA) on the causal association between dyslexia and AD. Two MVMR methods, including MV IVW and MV-Egger, and two-step MR were used to perform the analysis. Using IVW, we found a significant causal association between increased dyslexia and increased risk of AD (OR = 1.15, 95% CI: 1.04–1.28, P = 0.006), but not VD, LBD, FTD, or its four subtypes. MR-PRESSO further supported the statistically significant association between dyslexia and AD (OR = 1.15, 95% CI: 1.05–1.27, P = 0.006). All sensitivity analyses confirmed the reliability of causal estimates. Using MV IVW and mediation analysis, we found no causal relationship between dyslexia and AD after adjusting for CP but not EA, CP mediated the total effect of dyslexia on AD with a proportion of 46.32%. We provide genetic evidence to support a causal effect of increased dyslexia on increased risk of AD, which was largely mediated by CP. Reading activity may be a potential intervention strategy for AD by improving cognitive function.

Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.