Unraveling the causal relationships between depression and brain structural imaging phenotypes: A bidirectional Mendelian Randomization study.

BACKGROUND: Previous studies have revealed structural brain abnormalities in individuals with depression, but the causal relationship between depression and brain structure remains unclear. METHODS: A genetic correlation analysis was conducted using summary statistics from the largest genome-wide association studies for depression (N = 674,452) and 1,265 brain structural imaging-derived phenotypes (IDPs, N = 33,224). Subsequently, a bidirectional two-sample Mendelian Randomization (MR) approach was employed to explore the causal relationships between depression and the IDPs that showed genetic correlations with depression. The main MR results were obtained using the inverse variance weighted (IVW) method, and other MR methods were further employed to ensure the reliability of the findings. RESULTS: Ninety structural IDPs were identified as being genetically correlated with depression and were included in the MR analyses. The IVW MR results indicated that reductions in the volume of several brain regions, including the bilateral subcallosal cortex, right medial orbitofrontal cortex, and right middle-posterior part of the cingulate cortex, were causally linked to an increased risk of depression. Additionally, decreases in surface area of the right middle temporal visual area, right middle temporal cortex, right inferior temporal cortex, and right middle-posterior part of the cingulate cortex were causally associated with a heightened risk of depression. Validation and sensitivity analyses supported the robustness of these findings. However, no evidence was found for a causal effect of depression on structural IDPs. CONCLUSIONS: Our findings reveal the causal influence of specific brain structures on depression, providing evidence to consider brain structural changes in the etiology and treatment of depression.

Mapping the landscape: a bibliometric analysis of resting-state fMRI research on schizophrenia over the past 25 years.

Schizophrenia, a multifaceted mental disorder characterized by disturbances in thought, perception, and emotion, has been extensively investigated through resting-state fMRI, uncovering changes in spontaneous brain activity among those affected. However, a bibliometric examination regarding publication trends in resting-state fMRI studies related to schizophrenia is lacking. This study obtained relevant publications from the Web of Science Core Collection spanning the period from 1998 to 2022. Data extracted from these publications included information on countries/regions, institutions, authors, journals, and keywords. The collected data underwent analysis and visualization using VOSviewer software. The primary analyses included examination of international and institutional collaborations, authorship patterns, co-citation analyses of authors and journals, as well as exploration of keyword co-occurrence and temporal trend networks. A total of 859 publications were retrieved, indicating an overall growth trend from 1998 to 2022. China and the United States emerged as the leading contributors in both publication outputs and citations, with Central South University and the University of New Mexico being identified as the most productive institutions. Vince D. Calhoun had the highest number of publications and citation counts, while Karl J. Friston was recognized as the most influential author based on co-citations. Key journals such as Neuroimage, Schizophrenia Research, Schizophrenia Bulletin, and Biological Psychiatry played pivotal roles in advancing this field. Recent popular keywords included support vector machine, antipsychotic medication, transcranial magnetic stimulation, and related terms. This study systematically synthesizes the historical development, current status, and future trends in resting-state fMRI research in schizophrenia, offering valuable insights for future research directions.

Homotopic functional connectivity disruptions in schizophrenia and their associated gene expression.

It has been revealed that abnormal voxel-mirrored homotopic connectivity (VMHC) is present in patients with schizophrenia, yet there are inconsistencies in the relevant findings. Moreover, little is known about their association with brain gene expression profiles. In this study, transcription-neuroimaging association analyses using gene expression data from Allen Human Brain Atlas and case-control VMHC differences from both the discovery (meta-analysis, including 9 studies with a total of 386 patients and 357 controls) and replication (separate group-level comparisons within two datasets, including a total of 258 patients and 287 controls) phases were performed to identify genes associated with VMHC alterations. Enrichment analyses were conducted to characterize the biological functions and specific expression of identified genes, and Neurosynth decoding analysis was performed to examine the correlation between cognitive-related processes and VMHC alterations in schizophrenia. In the discovery and replication phases, patients with schizophrenia exhibited consistent VMHC changes compared to controls, which were correlated with a series of cognitive-related processes; meta-regression analysis revealed that illness duration was negatively correlated with VMHC abnormalities in the cerebellum and postcentral/precentral gyrus. The abnormal VMHC patterns were stably correlated with 1287 genes enriched for fundamental biological processes like regulation of cell communication, nervous system development, and cell communication. In addition, these genes were overexpressed in astrocytes and immune cells, enriched in extensive cortical regions and wide developmental time windows. The present findings may contribute to a more comprehensive understanding of the molecular mechanisms underlying VMHC alterations in patients with schizophrenia.

Transcriptional signatures of the whole-brain voxel-wise resting-state functional network centrality alterations in schizophrenia.

Neuroimaging studies have revealed that patients with schizophrenia exhibit disrupted resting-state functional connectivity. However, the inconsistent findings across these studies have hindered our comprehensive understanding of the functional connectivity changes associated with schizophrenia, and the molecular mechanisms associated with these alterations remain largely unclear. A quantitative meta-analysis was first conducted on 21 datasets, involving 1057 patients and 1186 healthy controls, to examine disrupted resting-state functional connectivity in schizophrenia, as measured by whole-brain voxel-wise functional network centrality (FNC). Subsequently, partial least squares regression analysis was employed to investigate the relationship between FNC changes and gene expression profiles obtained from the Allen Human Brain Atlas database. Finally, gene enrichment analysis was performed to unveil the biological significance of the altered FNC-related genes. Compared with healthy controls, patients with schizophrenia show consistently increased FNC in the right inferior parietal cortex extending to the supramarginal gyrus, angular gyrus, bilateral medial prefrontal cortex, and right dorsolateral prefrontal cortex, while decreased FNC in the bilateral insula, bilateral postcentral gyrus, and right inferior temporal gyrus. Meta-regression analysis revealed that increased FNC in the right inferior parietal cortex was positively correlated with clinical score. In addition, these observed functional connectivity changes were found to be spatially associated with the brain-wide expression of specific genes, which were enriched in diverse biological pathways and cell types. These findings highlight the aberrant functional connectivity observed in schizophrenia and its potential molecular underpinnings, providing valuable insights into the neuropathology of dysconnectivity associated with this disorder.

Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression.

Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.

A causal association of ANKRD37 with human hippocampal volume.

Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37 gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37 expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37 in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37 overexpression, and cg26741686 hypermethylation favored ANKRD37 overexpression, and ANKRD37 overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37 expression, and ANKRD37 expression with hippocampal volume could be replicated in an independent healthy young (n = 443) dataset and observed in elderly people (n = 194), and were more significant in patients with late-onset Alzheimer's disease (n = 76). This study revealed a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.

Sirt1 protects against hippocampal atrophy and its induced cognitive impairment in middle-aged mice.

BACKGROUND: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. RESULTS: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage. CONCLUSIONS: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

Oxytocin Nanogels Inhibit Innate Inflammatory Response for Early Intervention in Alzheimer's Disease.

Prevention of Alzheimer's disease (AD) is a global imperative, but reliable early interventions are currently lacking. Microglia-mediated chronic neuroinflammation is thought to occur in the early stage of AD and plays a critical role in AD pathogenesis. Here, oxytocin (OT)-loaded angiopep-2-modified chitosan nanogels (AOC NGs) were designed for early treatment of AD via inhibiting innate inflammatory response. Through the effective transcytosis of angiopep-2, AOC NGs were driven intravenously to cross the blood-brain barrier, enter the brain, and enrich in brain areas affected by AD. A large amount of OT was then released and specifically bound to the pathological upregulated OT receptor, thus effectively inhibiting microglial activation and reducing inflammatory cytokine levels through blocking the ERK/p38 MAPK and COX-2/iNOS NF-κB signaling pathways. Consecutive weekly intravenous administration of AOC NGs into 12-week-old young APP/PS1 mice, representing the early stage of AD, remarkably slowed the progression of Aß deposition and neuronal apoptosis in the APP/PS1 mice as they aged and ultimately prevented cognitive impairment and delayed hippocampal atrophy. Together, the findings suggest that AOC NGs, which show good biosafety, can serve as a promising therapeutic candidate to combat neuroinflammation for early prevention of AD.