Molecular Psychiatry最新文献

Postpartum psychosis (PP) is a severe psychiatric disorder–with limited data or consensus on diagnostic criteria and clinical presentation–that affects thousands of people each year. The Massachusetts General Hospital Postpartum Psychosis Project (MGHP3) was established to: 1) describe the phenomenology of PP, and 2) identify genomic and clinical predictors in a large cohort. Results thus far point to a richer understanding of the heterogeneity and complexity of this often-misunderstood illness and its nature over time. Data are collected from those who experienced PP within 6 months of delivery and within the 10 years prior to the MGHP3 interview. Participants provide information via the Mini International Neuropsychiatric Interview for Psychotic Disorders Studies (MINI-PDS), MGHP3© Questionnaire (including assessment of episode onset, duration, symptoms, and treatment received), and other relevant history. This retrospective study uses validated diagnostic tools to evaluate psychiatric history across participants’ lifetimes. Descriptive statistics (e.g., median values, frequencies) were conducted to describe the phenomenology of PP. As of November 3, 2022, 248 participants with histories of at least one episode of PP completed the MGHP3 interview. Most participants met criteria for Bipolar I Disorder with psychotic features (71.8%). During PP episode(s), participants reported odd beliefs or delusions (87.6%), persecutory delusions (75.2%), ideas of reference (55.8%), and visual (52.3%) and/or auditory (48.1%) hallucinations. The median time between delivery and symptom onset was 10 days (SD = 43.72). Most participants reported receiving medication (93.0%) and/or psychotherapy (65.9%). This report describes findings regarding the phenomenology of postpartum psychosis among the MGHP3 cohort, the largest cohort with validated PP studied to date. This ongoing effort to refine the phenotype of PP and to delineate underlying genetic determinants of the disorder will contribute to an enhanced understanding of this serious illness. It also underscores areas for further rigorous assessment using other research methods and sets the stage for translational reproductive neuroscience – including ongoing analyses of neuroimaging and genetic data from the MGHP3 cohort.

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K–Akt–mTORC1–p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

Background/objectives

Dysregulation of molecular pathways associated with mechanistic target of rapamycin (mTOR) and elevated rates of neurodevelopmental disorders are implicated in the genetic syndromes neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Noonan syndrome (NS). Given shared molecular and clinical features, understanding convergent and divergent implications of these syndromes on brain development may offer unique insights into disease mechanisms. While an increasing number of studies have examined brain volumes in these syndromes, the effects of each syndrome on global and subcortical brain volumes are unclear. Therefore, the aim of the current study was to conduct a systematic review and meta-analysis to synthesize existing literature on volumetric brain changes across TSC, FXS, NF1, and NS. Study outcomes were the effect sizes of the genetic syndromes on whole brain, gray and white matter, and subcortical volumes compared to typically developing controls.

Subjects/methods

We performed a series of meta-analyses synthesizing data from 23 studies in NF1, TSC, FXS, and NS (pooled N = 1556) reporting whole brain volume, gray and white matter volumes, and volumes of subcortical structures compared to controls.

Results

Meta-analyses revealed significantly larger whole brain volume, gray and white matter volumes, and subcortical volumes in NF1 compared to controls. FXS was associated with increased whole brain, and gray and white matter volumes relative to controls, but effect sizes were smaller than those seen in NF1. In contrast, studies in NS indicated smaller whole brain and gray matter volumes, and reduced subcortical volumes compared to controls. For individuals with TSC, there were no significant differences in whole brain, gray matter, and white volumes compared to controls. Volumetric effect sizes were not moderated by age, sex, or full-scale IQ.

Conclusions

This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [¹⁸F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [¹⁸F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R² = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R² = 0.16, p = 0.01). Topographic correspondence analysis with the [¹⁸F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.

Background

Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the in-utero environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.

Methods

The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.

Results

Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.

Conclusions

Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10⁻⁸) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10⁻⁶). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

Catatonia is a severe psychomotor disorder characterized by motor, affective and cognitive-behavioral abnormalities. Although previous magnetic resonance imaging (MRI) studies suggested white matter (WM) dysconnectivity in the pathogenesis of catatonia, it is unclear whether microstructural alterations of WM tracts connecting psychomotor regions might contribute to a better classification of catatonia patients. Here, diffusion-weighted MRI data were collected from two independent cohorts (whiteCAT/replication cohort) of patients with (n = 45/n = 13) and without (n = 56/n = 26) catatonia according to ICD-11 criteria. Catatonia severity was examined using the Northoff (NCRS) and Bush-Francis (BFCRS) Catatonia Rating Scales. We used tract-based spatial statistics (TBSS), tractometry (TractSeg) and machine-learning (ML) to classify catatonia patients from tractometry values as well as tractomics features generated by the newly developed tool RadTract. Catatonia patients showed fractional anisotropy (FA) alterations measured via TractSeg in different corpus callosum segments (CC_1, CC_3, CC_4, CC_5 and CC_6) compared to non-catatonia patients across both cohorts. Our classification results indicated a higher level of performance when trained on tractomics as opposed to traditional tractometry values. Moreover, in the CC_6, we successfully trained two classifiers using the tractomics features identified in the whiteCAT data. These classifiers were applied separately to the whiteCAT and replication cohorts, demonstrating comparable performance with Area Under the Receiver Operating Characteristics (AUROC) values of 0.79 for the whiteCAT cohort and 0.76 for the replication cohort. In contrast, training on FA tractometry resulted in lower AUROC values of 0.66 for the whiteCAT cohort and 0.51 for the replication cohort. In conclusion, these findings underscore the significance of CC WM microstructural alterations in the pathophysiology of catatonia. The successful use of an ML based classification model to identify catatonia patients has the potential to improve diagnostic precision.