Translational Psychiatry最新文献

Recents findings suggest that the ghrelin/LEAP2 (Liver Expressed Antimicrobial Peptide 2) ratio impacts the dynamics of reward sensitivity, and that LEAP2 may serve as a biomarker of remission in patients with anorexia nervosa (AN). We hypothesized that the ghrelin/LEAP2 ratio influences impulsive food choices following chronic food restriction and refeeding. Impulse control and plasma ghrelin and LEAP2 concentrations were evaluated in a longitudinal study of 30 female patients with AN after weight restoration and 6-months following discharge to evaluate their weight gain status. Cognitive impulsivity was also assessed in young C57Bl6/J female mice at baseline, after 15 days of 50% quantitative food restriction and after 10 days of refeeding. We collected blood for ghrelin and LEAP2 measurement and brain structures involved in metabolic response, reward and cognitive control. The ghrelin/LEAP2 ratio was negatively correlated with impulse control in patients after weight restoration, but only in those who maintained stable weight gain after discharge. In mice, food restriction increased cognitive impulsivity and refeeding only partially restored this phenotype compared to control conditions. Cognitive impulsivity was also positively correlated with plasma LEAP2 levels but not with the expression of the key hypothalamic neuropeptides or mesocorticolimbic dopamine DRD1/DRD2 receptors. Our results suggest that the interaction between LEAP2 and cognitive impulsivity is affected by changes in nutritional status in patients and female mice. Metabolic and cognitive consequences of food restriction may influence how food choices are modified in patients with AN and may be associated with a greater likelihood of achieving stable weight gain. Schematic representation of the current findings and hypothesis regarding the role of the ghrelin/LEAP2 ratio on the modulation of cognitive impulsivity following refeeding and its effects on weight gain stability in AN.

Fatigue is a pervasive and difficult-to-treat symptom of major depressive disorder (MDD) that contributes to disability. Understanding this problem in its earlier stages will be critical for averting long-term negative outcomes. To investigate the molecular roots of fatigue in early-stage depression, the current work measured bioenergetic mechanisms, with a focus on adenosine triphosphate (ATP), in brain and blood cells in young adults with MDD versus healthy controls (HC). To measure ATP concentration and ATP production rate in the visual cortex, we utilized ³¹P magnetic resonance spectroscopy imaging with magnetization transfer (³¹P MRSI-MT) at 7 Tesla, with and without gamma-ATP resonance saturation. ATP level was also measured in peripheral blood mononuclear cells (PBMCs) at rest and after serial addition of mitochondrial inhibitors. Out of 25 participants (mean age 21.8 years), usable data were available for 18 participants for imaging (9 per group); 24 for PBMCs (13 HC; 11 MDD). The MDD group demonstrated higher ATP production rate in the visual cortex than HC, which correlated positively with Fatigue Severity Scale (FSS) scores. ATP concentrations in PBMCs were higher in MDD than HC, and also correlated with FSS scores. After mitochondrial uncoupling, PBMCs in the MDD group had a lower capacity for ATP production than HC. For the first time, we demonstrate an ATP biosignature of fatigue in young adults with MDD that is visible in both brain and peripheral blood. The findings suggest a compensatory mechanism that occurs early in the disease stage.

White matter hyperintensities (WMHs) are common in Alzheimer's disease (AD) and may contribute to cognitive impairment. However, the associations between regional WMH volumes, cognitive domains, and plasma biomarkers remain unclear. This study aimed to explore these relationships across the AD spectrum. A total of 311 participants were enrolled, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. All participants underwent comprehensive neuropsychological assessment, brain magnetic resonance imaging, and plasma biomarker analysis. WMH volumes were segmented using United Imaging software and classified based on anatomical location: juxtaventricular WMH (juxWMH), periventricular WMH (pWMH), juxtacortical WMH (jcWMH), and deep WMH (dWMH). Correlations among regional WMH volumes, plasma biomarkers, and cognitive domains were analyzed with multiple comparisons. Path analysis was used to assess potential mediation effects. Mediation analyses using bootstrapping were conducted separately in cognitively unimpaired and cognitively impaired groups to assess WMH-mediated pathways between biomarkers and cognition. Compared with HC, SCD, and MCI groups, the AD group showed significantly increased log-transformed (lg) juxWMH volumes (all P < 0.05, Bonferroni corrected). The AD group showed significantly larger lgpWMH and lgjcWMH volumes than HC, SCD and AD groups (all P < 0.05). Lower plasma Aβ42/Aβ40 ratio was associated with higher lgjuxWMH, lgpWMH, and lgjcWMH volumes. Higher lgjuxWMH volume was associated with worse memory (r = -0.16, P = 0.006), language (r = -0.34, P < 0.001), and executive function (r = 0.18, P = 0.003). Similar trends were found for lgpWMH and lgjcWMH volumes. Mediation analysis revealed that in cognitively unimpaired individuals, juxWMH and pWMH primarily mediated amyloid-cognitive associations, while in cognitively impaired patients, mediation expanded to include neuroinflammatory and neurodegeneration pathways across multiple location-specific WMH. Location-specific WMH demonstrate stage-dependent mediation patterns in AD pathophysiology, evolving from amyloid-driven changes to multi-factorial processes. These findings provide insights for developing targeted therapeutic strategies at different disease stages.

Maternal immune activation (MIA) during pregnancy may increase the risk for neurodevelopmental disorders such as schizophrenia and autism in offspring. Preclinical and human evidence support a potential role for MIA in the development of depressive symptoms in offspring. Among animal models of MIA, prenatal treatment with the synthetic viral mimetic polyinosinic-polycytidylic acid [poly (I:C)] is well established in studying psychotic-like and autism-like phenotypes, while its validity for modeling depressive-like behaviors remains underexplored. In this study, we assessed whether MIA, induced in rats with an injection of high molecular weight (HMW) poly (I:C), at gestational day 15, leads to a depressive-like phenotype in the offspring. In male and female offspring during adolescence and adulthood, we evaluated i) behavioral despair and anhedonia using the forced swim test (FST) and sucrose preference test (SPT); ii) the electrophysiological properties of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in vivo; iii) serum cytokine profile. We found that MIA offspring exhibited increased immobility and reduced climbing and swimming in the FST, with more pronounced effects in males, while sucrose preference remained unaltered. In vivo recordings revealed a significant increase in 5-HT neuron firing rate in MIA adult males. Peripheral cytokine analysis showed elevated IL-1α in MIA males and decreased GRO/KC levels in MIA females. In conclusion, these findings indicate that prenatal exposure to HMW poly (I:C) selectively affects stress-coping mechanisms without inducing anhedonia, modulates serotonergic signaling in a sex- dependent manner in the absence of widespread inflammatory alterations.

In multiple sclerosis (MS), functional network abnormalities arise as structural damage accumulates. However their biological basis and spatial distribution remain unclear. This study investigated the associations between MS-related functional network abnormalities and physiological gene expression using the Allen Human Brain Atlas (AHBA). Five-hundred fifty-eight MS patients and 214 healthy controls (HC) underwent neurological assessment and 3 T MRI; 491 patients also completed a neuropsychological evaluation. Resting-state functional MRI was used to generate degree centrality maps to identify network topography alterations. Spatial correlations between centrality abnormalities (p < 0.01 uncorrected) and the expression of 3634 MS-related genes was evaluated using AHBA and the Multimodal Environment for Neuroimaging and Genomic Analysis. Genes showing significant associations (p < 0.001, R² ≥ 0.15) underwent pathway enrichment analysis (p < 0.05, Bonferroni-corrected). Compared to HC, MS patients showed higher centrality mainly in the default-mode network (DMN), linked to genes regulating inflammation resolution and immune functions, and lower centrality in regions mostly located in the salience network and cerebellum, associated with genes implicated in cytokine response. Compared to HC and relapsing-remitting MS, progressive MS patients showed higher centrality in DMN and cerebellar regions, correlating with genes related to epigenetic and mitochondrial functions. Of the MS cohort, 144 (29.3%) patients were cognitively impaired. Compared to cognitively preserved MS and HC, they showed higher centrality in DMN and mesial temporal lobe regions, negatively correlated with expression of DNASE1, regulating DNA degradation, and CP, encoding ceruloplasmin, involved in iron homeostasis and potentially iron-driven neurodegeneration. Physiological regional gene expression spatially correlates with MS-related functional network alterations. Biological factors may shape regional vulnerability or resilience to MS pathology, influencing functional reorganization.

Background: Despite decades of research, the underlying mechanism of auditory verbal hallucinations (AVH), a core symptom of schizophrenia, remain unclear. Previous studies have tried to capture the neural activity during AVH episodes, whereas trait features of AVH have been less investigated. To address this gap, we employed functional Near-Infrared Spectroscopy (fNIRS) to investigate the neuroimaging patterns in healthy controls (HCs), patients with schizophrenia with a history of AVH (AVHh+) and those without a history of AVH history (AVHh-). We hypothesized that significant differences of functional connectivity (FC) changes would be observed in AVHh+.

Method: We recruited 23 AVHh+, 16 AVHh-, and 17 matched HCs. Participants underwent an 8-minute resting-state fNIRS scanning. Data processing and analysis were conducted by the NirSpark software (HuiChuang, China) package and R Studio.

Result: Compared to the AVHh-, the AVHh+ showed significantly lower FC between the Broca's area and the left supplementary motor area (SMA).

Conclusion: The hypoconnectivity of Broca-left SMA circuit might serve as a trait-like marker of vulnerability to AVH.

Working memory (WM) deficits are commonly observed across the depression spectrum and may represent a modifiable cognitive mechanism. This systematic review and meta-analysis evaluated the effects of WM training (WMT) on depressive symptoms and WM performance, and examined potential moderators and the association between WM gains and symptom change. Systematic searches of PsycINFO, Embase, and PubMed were conducted in December 2022 and updated in January 2025. Eligible studies were randomized controlled trials (RCTs) using WMT as the sole cognitive intervention with depressive symptoms as outcomes. Two-level random-effects models were used for depressive symptoms and three-level models for WM outcomes. Risk of bias was assessed by the Cochrane Risk of Bias Tool. Twenty-seven RCTs involving 1692 participants were included. WMT produced a small but significant reduction in depressive symptoms at post-training (Hedges' g = 0.20, 95% CI [0.04, 0.35]), though effect was not maintained at follow-up. Moderate improvements in WM were observed at post-training (g = 0.61, 95% CI [0.24, 0.98]) and follow-up (g = 0.72, 95% CI [0.07, 1.38]). Post-training WM gains were positively associated with symptom reductions at follow-up. Moderator analyses indicated that baseline symptom severity and training material valence may influence outcomes, though subgroup effects were not statistically significant and warrant cautious interpretation. These findings suggest that WMT targets a potentially modifiable mechanism in depression, but its clinical utility remains uncertain. Larger RCTs, particularly in clinical populations and with extended follow-ups, are needed to establish more definitive evidence regarding its preventive and therapeutic value. (Protocol registration: PROSPERO, CRD42023400213.).

Alzheimer's disease (AD) is a heterogeneous disorder with individual variability in clinical and biological features. Mild cognitive impairment (MCI) represents transition phase and provides a critical window for early intervention. Clinically applicable metrics for quantifying individual brain structural variations remain limited. This study aimed to delineate neuroanatomical heterogeneity and identify brain structural subtypes using individual deviation analysis. We constructed normative models of regional gray matter volume across lifespan using T1-weighted MRI data from 1185 healthy controls in the Cam-CAN and OASIS-3 cohorts. Individual deviations from normative trajectories were evaluated for AD and MCI patients in the ADNI dataset. Based on deviation patterns, unsupervised clustering analysis was used to identify distinct AD and MCI subtypes. Clinical features, longitudinal progression, and gene expression profiles were evaluated for each subtype. We found that substantial heterogeneity in the spatial distribution and severity of structural abnormalities across individuals. Two robust subtypes were identified in each group. Subtype 2 of AD and MCI showed more pronounced negative deviation patterns than subtype 1, particularly in the hippocampus, parahippocampal gyrus, and amygdala. These subtypes demonstrated significant differences in cognitive performance, biomarker profiles, disease progression, and gene expression patterns. AD and MCI subtypes exhibited similar deviation patterns, and MCI subtype with more severe negative deviations had a higher risk of converting to AD. This study reveals the neuroanatomical heterogeneity of AD and MCI and demonstrates that individualized deviation mapping can detect clinically valuable subtypes. These findings provide a foundation for personalized diagnosis and monitoring strategies in neurodegenerative diseases.

Stimulants are the first-line pharmacological treatment for ADHD and generally effective, yet 35-61% of individuals discontinue treatment within a year. We investigated the contribution of common and rare genetic variants to early stimulant discontinuation using data from 18,362 individuals with ADHD (31% female) initiating stimulants in iPSYCH, a Danish population-based case-cohort linked to national registers. Discontinuation was defined as a ≥ 180-day gap between dispensations within one year of initiation. We examined genetic differences by age groups, estimated SNP-heritability (h²_SNP), conducted genome-wide association studies (GWAS), polygenic score (PGS) analyses, and assessed associations with protein truncating variants (PTV). Within one year, 7102 individuals (39%) had discontinued stimulants. Age-stratified analyses (cut-off: age 16) revealed low genetic correlation (r₉ = 0.23, 95% CI: -0.37, 0.83) between children and adolescents/adults. The h²_snp for discontinuation was 0.06 (95% CI: 0.02, 0.11) overall, 0.08 (95% CI: 0.02, 0.14) in children, and 0.14 (95% CI: 0.02, 0.27) in adolescents/adults. No genome-wide significant loci were identified overall or in adolescents/adults; however, one locus (SLC5A12, chromosome 11) reached genome-wide significance in children. Ten of 36 PGSs were associated with discontinuation, with higher psychiatric risk PGSs predicting increased discontinuation, while educational attainment and BMI PGSs showed divergent effects by age. Reduced burden of dopamine-related PTVs was nominally associated with discontinuation, particularly in adolescents/adults. These findings suggest modest contributions of both common and rare variants to stimulant discontinuation in ADHD and point to potential developmental differences in genetic architecture.

In this longitudinal study, 37 patients with severe alcohol use disorder (SAUD) were tested at the beginning (T1) and end (T2) of supervised detoxification to explore the evolution of and relationship between systemic inflammation, volumetric changes for brain grey matter (GM) and choroid plexus (ChP), and clinical symptoms. At T1, patients exhibited high levels of anxiety, depression, and craving, and had elevated plasmatic pro-inflammatory cytokines, indicating low-grade systemic inflammation. Monocyte chemoattractant protein-1 (CCL2) (MCP-1) levels correlated positively with ChP volume and severity of withdrawal symptoms, while macrophage inflammatory protein-1 beta (CCL4) (MIP-1β) also correlated with ChP volume, together suggesting an acute immune response at T1, and underscoring the ChP as a potential neuroimmune biomarker to be further evaluated in future studies. During three weeks' abstinence, Interleukin-8 (IL-8), MIP-1β, and MCP-1 levels decreased, although MIP-1β did not return to control levels, and tumor necrosis factor-alpha (TNF-α) showed no significant reduction. Volumetric MRI analyses suggested two concurrent trajectories during detoxification. First, an overall "recovery-driven" pattern of rapidly increasing GM volume in widespread forebrain regions with parallel declines in ventricle size and craving. Second, GM in limbic cortical areas, temporal and inferior frontal cortex showed no significant volumetric gain. However, these regional volumes correlated significantly with declining MCP-1, indicative of a "deflation", potentially related to declining microglial activation. These findings highlight the role of inflammatory processes in shaping early neuroplastic changes during detoxification and point to a central role of MCP-1 in inflammation-driven morphometric changes.