Neuroticism polygenic risk predicts conversion from mild cognitive impairment to Alzheimer's disease by impairing inferior parietal surface area.

The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.

A multimodal prediction model for suicidal attempter in major depressive disorder.

Background: Suicidal attempts in patients with major depressive disorder (MDD) have become an important challenge in global mental health affairs. To correctly distinguish MDD patients with and without suicidal attempts, a multimodal prediction model was developed in this study using multimodality data, including demographic, depressive symptoms, and brain structural imaging data. This model will be very helpful in the early intervention of MDD patients with suicidal attempts. Methods: Two feature selection methods, support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) algorithms, were merged for feature selection in 208 MDD patients. SVM was then used as a classification model to distinguish MDD patients with suicidal attempts or not. Results: The multimodal predictive model was found to correctly distinguish MDD patients with and without suicidal attempts using integrated features derived from SVM-RFE and RF, with a balanced accuracy of 77.78%, sensitivity of 83.33%, specificity of 70.37%, positive predictive value of 78.95%, and negative predictive value of 76.00%. The strategy of merging the features from two selection methods outperformed traditional methods in the prediction of suicidal attempts in MDD patients, with hippocampal volume, cerebellar vermis volume, and supracalcarine volume being the top three features in the prediction model. Conclusions: This study not only developed a new multimodal prediction model but also found three important brain structural phenotypes for the prediction of suicidal attempters in MDD patients. This prediction model is a powerful tool for early intervention in MDD patients, which offers neuroimaging biomarker targets for treatment in MDD patients with suicidal attempts.

Interfacial-Catalysis-Enabled Layered and Inorganic-Rich SEI on Hard Carbon Anodes in Ester Electrolytes for Sodium-Ion Batteries.

Constructing a homogenous and inorganic-rich solid electrolyte interface (SEI) can efficiently improve the overall sodium-storage performance of hard carbon (HC) anodes. However, the thick and heterogenous SEI derived from conventional ester electrolytes fails to meet the above requirements. Herein, an innovative interfacial catalysis mechanism is proposed to design a favorable SEI in ester electrolytes by reconstructing the surface functionality of HC, of which abundant CO (carbonyl) bonds are accurately and homogenously implanted. The CO (carbonyl) bonds act as active centers that controllably catalyze the preferential reduction of salts and directionally guide SEI growth to form a homogenous, layered, and inorganic-rich SEI. Therefore, excessive solvent decomposition is suppressed, and the interfacial Na+ transfer and structural stability of SEI on HC anodes are greatly promoted, contributing to a comprehensive enhancement in sodium-storage performance. The optimal anodes exhibit an outstanding reversible capacity (379.6 mAh g-1 ), an ultrahigh initial Coulombic efficiency (93.2%), a largely improved rate capability, and an extremely stable cycling performance with a capacity decay rate of 0.0018% for 10 000 cycles at 5 A g-1 . This work provides novel insights into smart regulation of interface chemistry to realize high-performance HC anodes for sodium storage.

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.

Associations of Polygenic Risk Score for Late-Onset Alzheimer's Disease With Biomarkers.

Late-onset Alzheimer's disease (LOAD) is a common irreversible neurodegenerative disease with heterogeneous genetic characteristics. Identifying the biological biomarkers with the potential to predict the conversion from normal controls to LOAD is clinically important for early interventions of LOAD and clinical treatment. The polygenic risk score for LOAD (AD-PRS) has been reported the potential possibility for reliably identifying individuals with risk of developing LOAD recently. To investigate the external phenotype changes resulting from LOAD and the underlying etiology, we summarize the comprehensive associations of AD-PRS with multiple biomarkers, including neuroimaging, cerebrospinal fluid and plasma biomarkers, cardiovascular risk factors, cognitive behavior, and mental health. This systematic review helps improve the understanding of the biomarkers with potential predictive value for LOAD and further optimizing the prediction and accurate treatment of LOAD.

Structural and functional biomarkers of the insula subregions predict sex differences in aggression subscales.

Aggression is a common and complex social behavior that is associated with violence and mental diseases. Although sex differences were observed in aggression, the neural mechanism for the effect of sex on aggression behaviors remains unclear, especially in specific subscales of aggression. In this study, we investigated the effects of sex on aggression subscales, gray matter volume (GMV), and functional connectivity (FC) of each insula subregion as well as the correlation of aggression subscales with GMV and FC. This study found that sex significantly influenced (a) physical aggression, anger, and hostility; (b) the GMV of all insula subregions; and (c) the FC of the dorsal agranular insula (dIa), dorsal dysgranular insula (dId), and ventral dysgranular and granular insula (vId_vIg). Additionally, mediation analysis revealed that the GMV of bilateral dIa mediates the association between sex and physical aggression, and left dId-left medial orbital superior frontal gyrus FC mediates the relationship between sex and anger. These findings revealed the neural mechanism underlying the sex differences in aggression subscales and the important role of the insula in aggression differences between males and females. This finding could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior.

Global urbanicity is associated with brain and behaviour in young people.

Urbanicity is a growing environmental challenge for mental health. Here, we investigate correlations of urbanicity with brain structure and function, neuropsychology and mental illness symptoms in young people from China and Europe (total n = 3,867). We developed a remote-sensing satellite measure (UrbanSat) to quantify population density at any point on Earth. UrbanSat estimates of urbanicity were correlated with brain volume, cortical surface area and brain network connectivity in the medial prefrontal cortex and cerebellum. UrbanSat was also associated with perspective-taking and depression symptoms, and this was mediated by neural variables. Urbanicity effects were greatest when urban exposure occurred in childhood for the cerebellum, and from childhood to adolescence for the prefrontal cortex. As UrbanSat can be generalized to different geographies, it may enable assessments of correlations of urbanicity with mental illness and resilience globally.

Crystal Phase-Controlled Modulation of Binary Transition Metal Oxides for Highly Reversible Li-O2 Batteries.

Reducing charge-discharge overpotential of transition metal oxide catalysts can eventually enhance the cell efficiency and cycle life of Li-O2 batteries. Here, we propose that crystal phase engineering of transition metal oxides could be an effective way to achieve the above purpose. We establish controllable crystal phase modulation of the binary MnxCo1-xO by adopting a cation regulation strategy. Systematic studies reveal an unprecedented relevancy between charge overpotential and crystal phase of MnxCo1-xO catalysts, whereas a dramatically reduced charge overpotential (0.48 V) via a rational optimization of Mn/Co molar ratio = 8/2 is achieved. Further computational studies indicate that the different morphologies of Li2O2 should be related to different electronic conductivity and binding of Li2O2 on crystal facets of MnxCo1-xO catalysts, finally leading to different charge overpotential. We anticipate that this specific crystal phase engineering would offer good technical support for developing high-performance transition metal oxide catalysts for advanced Li-O2 batteries.

Predicting Drug-Disease Associations via Multi-Task Learning Based on Collective Matrix Factorization.

Identifying drug-disease associations is integral to drug development. Computationally prioritizing candidate drug-disease associations has attracted growing attention due to its contribution to reducing the cost of laboratory screening. Drug-disease associations involve different association types, such as drug indications and drug side effects. However, the existing models for predicting drug-disease associations merely concentrate on independent tasks: recommending novel indications to benefit drug repositioning, predicting potential side effects to prevent drug-induced risk, or only determining the existence of drug-disease association. They ignore crucial prior knowledge of the correlations between different association types. Since the Comparative Toxicogenomics Database (CTD) annotates the drug-disease associations as therapeutic or marker/mechanism, we consider predicting the two types of association. To this end, we propose a collective matrix factorization-based multi-task learning method (CMFMTL) in this paper. CMFMTL handles the problem as multi-task learning where each task is to predict one type of association, and two tasks complement and improve each other by capturing the relatedness between them. First, drug-disease associations are represented as a bipartite network with two types of links representing therapeutic effects and non-therapeutic effects. Then, CMFMTL, respectively, approximates the association matrix regarding each link type by matrix tri-factorization, and shares the low-dimensional latent representations for drugs and diseases in the two related tasks for the goal of collective learning. Finally, CMFMTL puts the two tasks into a unified framework and an efficient algorithm is developed to solve our proposed optimization problem. In the computational experiments, CMFMTL outperforms several state-of-the-art methods both in the two tasks. Moreover, case studies show that CMFMTL helps to find out novel drug-disease associations that are not included in CTD, and simultaneously predicts their association types.

Au-Ag Nanoclusters/3,3',5,5' Tetramethylbenzidine Complex as a Sensitive "Turn-On" Fluorescent Nanoplatform for Mercury (II) Ions Sensing.

Fluorescent bimetallic Au-Ag nanoclusters (Au-AgNCs) were found to exhibit oxidase-like activity and could catalyze the oxidation of 3,3',5,5' tetramethylbenzidine (TMB) to oxTMB. On the basis of this property, we assembled a fluorescent nanoplatform as a turn-on probe for sensing mercury (II) ions (Hg2+) through the inner-filter effect (IFE). Au-AgNCs and oxTMB were chosen as IFE absorber and fluorophore pair for the first time. In the absence of Hg2+, the Au-AgNCs absorption band well. Covered the fluorescence emission band of oxTMB, and as a result, the fluorescence of oxTMB was reduced. In the presence of Hg2+, Hg2+ was reduced to Hg0 by extra BSA in Au-AgNCs probe system and anchored on the surface of Au-AgNCs. The absorption intensity for Au-AgNCs then decreased at 418 nm, resulting in the recovery of fluorescence from oxTMB. The formed Au-Hg thin amalgam layer obviously enhanced the oxidase-like activity of Au-AgNCs as well as hindered the IFE activity between Au-AgNCs and oxTMB. Therefore, based on the Hg2+ stimulating oxidaselike properties of Au-AgNCs, a fluorometric assay for determination of Hg2+ was developed in this study. The proposed sensing strategy showed a linear range from 10 nM to 500 nM, with ultralow LOD of ~0.7 nM for Hg2+. Moreover, the detection probe system was stable over a wide pH range, making it able to be applied in complex sample systems. We have successfully demonstrated the detection of Hg2+ in tap water samples. The fluorescent assay reported here, for sensitive and selective determination of Hg2+, may find great application in multiple areas, such as environmental and pharmaceutical analysis.

Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment.

Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer's disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer's disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer's disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein-protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer's disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer's disease.

Acute autonomic neuropathy with severe gastrointestinal symptoms in children: a case series.

BACKGROUND: Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved. METHODS: A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN. RESULT: The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid. CONCLUSION: The clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

Prefrontal Volume Mediates Effect of COMT Polymorphism on Interference Resolution Capacity in Healthy Male Adults.

There exist gender differences in the modulation of catechol-O-methyltransferase (COMT) Val158Met polymorphism on cognitive performance; however, the underlying gene-anatomy-cognition pathways remain unknown. Here we hypothesize that prefrontal volume may mediate the modulation of COMT Val158Met polymorphism on interference resolution capacity in a gender-dependent manner. In 261 healthy young human subjects (143 males and 118 females), a 2-way analysis of variance showed a COMT × gender interaction (P = 0.023) on interference resolution capacity. Val/Val subjects performed worse in Stroop interference test than Met/Met subjects only in males (P = 0.028). Voxel-wise analysis in the whole brain also exhibited a COMT × gender interaction on gray matter volume (GMV) in the left lateral frontal pole (FP). Val/Val male individuals exhibited significantly decreased GMV in the left lateral FP than Val/Met (P = 0.003) and Met/Met (P = 0.006) male carriers. Mediation analysis revealed that the GMV of the left lateral FP mediated the association between COMT polymorphism and interference resolution in males. These findings provide a gene-anatomy-cognition pathway to describe how COMT Val158Met polymorphism affects interference resolution capacity via modulating the prefrontal GMV in healthy male subjects.

Cortical thickness development of human primary visual cortex related to the age of blindness onset.

Blindness primarily induces structural alteration in the primary visual cortex (V1). Some studies have found that the early blind subjects had a thicker V1 compared to sighted controls, whereas late blind subjects showed no significant differences in the V1. This implies that the age of blindness onset may exert significant effects on the development of cortical thickness of the V1. However, no previous research used a trajectory of the age of blindness onset-related changes to investigate these effects. Here we explored this issue by mapping the cortical thickness trajectory of the V1 against the age of blindness onset using data from 99 blind individuals whose age of blindness onset ranged from birth to 34 years. We found that the cortical thickness of the V1 could be fitted well with a quadratic curve in both the left (F = 11.59, P = 3 × 10-5) and right hemispheres (F = 6.54, P = 2 × 10-3). Specifically, the cortical thickness of the V1 thinned rapidly during childhood and adolescence and did not change significantly thereafter. This trend was not observed in the primary auditory cortex (A1), primary motor cortex (M1), or primary somatosensory cortex (S1). These results provide evidence that an onset of blindness before adulthood significantly affects the cortical thickness of the V1 and suggest a critical period for cortical development of the human V1.

Parcellation of the primary cerebral cortices based on local connectivity profiles.

Connectivity-based parcellation using diffusion MRI has been extensively used to parcellate subcortical areas and the association cortex. Connectivity profiles are vital for connectivity-based parcellation. Two categories of connectivity profiles are generally utilized, including global connectivity profiles, in which the connectivity information is from the seed to the whole brain, and long connectivity profiles, in which the connectivity information is from the seed to other brain regions after excluding the seed. However, whether global or long connectivity profiles should be applied in parcellating the primary cortex utilizing connectivity-based parcellation is unclear. Many sources of evidence have indicated that the primary cerebral cortices are composed of structurally and functionally distinct subregions. Because the primary cerebral cortices are rich in local anatomic hierarchical connections and possess high degree of local functional connectivity profiles, we proposed that local connectivity profiles, that is the connectivity information within a seed region of interest, might be used for parcellating the primary cerebral cortices. In this study, the global, long, and local connectivity profiles were separately used to parcellate the bilateral M1, A1, S1, and V1. We found that results using the three profiles were all quite consistent with reported cytoarchitectonic evidence. More importantly, the results using local connectivity profiles showed less inter-subject variability than the results using the other two, a finding which suggests that local connectivity profiles are superior to global and long connectivity profiles for parcellating the primary cerebral cortices. This also implies that, depending on the characteristics of specific areas of the cerebral cortex, different connectivity profiles may need to be adopted to parcellate different areas.

Neuroglobin up-regulation after ischaemic pre-conditioning in a rat model of middle cerebral artery occlusion.

PRIMARY OBJECTIVE: Neuroglobin (NGB) is a known neuroprotector and is up-regulated after ischaemia-hypoxia brain damage. However, no studies have investigated NGB levels after ischaemic pre-conditioning and middle cerebral artery occlusion (MCAO). METHODS AND PROCEDURES: This study subjected rats to different ischaemic pre-conditioning and MCAO regimens and assayed NGB levels in the hippocampus, cortex and hypothalamus by immunohistochemistry, quantitative polymerase chain reaction (PCR) and western blot. MAIN OUTCOMES AND RESULTS: After 30 minutes of ischaemic pre-conditioning, the number of NGB-positive cells and NGB levels in the hippocampus, cortex and hypothalamus were increased with longer reperfusion times, peaked at 24-hours reperfusion and slightly decreased at 48-hours reperfusion. Similarly, the mRNA and protein expression levels of NGB were also up-regulated; they peaked at 24-hours reperfusion and slightly decreased at 48-hours reperfusion. CONCLUSIONS: NGB may regulate neuroprotection against ischaemia and hypoxia-mediated brain damage after ischaemic pre-conditioning. The results provide additional evidence supporting the utility of ischaemic pre-conditioning and help elucidate its potential regulatory mechanism.

[Signal transduction pathway mediated by thrombopoietin in the inflammation model of microglia].

OBJECTIVE: To explore the signal transduction pathway mediated by thrombopoietin (TPO) in the inflammation model of microglia induced by lipopolysaccharide (LPS). METHODS: The inflammation model of microglia BV2 cells was prepared by LPS of 0.5 and 1.0 µg/mL stimulation. The expression of TPO and ERK mRNA in BV2 cells was detected by real time quantitative PCR. Western blot was used to evaluate the expression of TPO and ERK protein in BV2 cells. TPO and IL-6 contents in the culture supernatant fluid were measured using ELISA. RESULTS: LPS stimulation increased significantly the mRNA and protein expression of TPO and ERK in BV2 cells, especially at the concentration of 1.0 µg/mL for 12 hrs stimulation. There was a significant positive correlation between the mRNA and protein expression of TPO and ERK. CONCLUSIONS: Signal transduction pathway of ERK1/2 participates in the activation of TPO in inflammatory injury of BV2 cells.

[The neuroprotective effects and its mechanisms of qingkailing injection on bacterial meningitis induced by E. coli in rabbits].

OBJECTIVE: To explore the neuro-protective effect and mechanism of qingkailing injection (QKL) against cerebral injury caused by E. coli-meningitis (CM). METHODS: The CM model rabbits were treated by ampicillin with QKL as adjuvant. The leukocyte count and protein content in cerebral spinal fluid (CSF), the contents of water, sodium, potassium and calcium in cerebral tissues were measured before, 16 h and 26 h after Bacillus coli injection respectively. The expression of matrix metalloproteinase-9 (MMP-9) was determined at the same time. RESULTS: Adjunctive treatment with QKL can not only inhibit the increase of leukocyte cells, protein content in CSF, and water, sodium, calcium content in cerebral tissues, but also the decrease of potassium content revealed during simple antibiotic treatment. It also can decrease the expression of MMP-9 in cerebral tissues of rabbits with CM. CONCLUSION: As an adjunctive treatment, QKL can prevent transient inflammatory reaction and aggravation of brain injury in CM induced by simple antibiotic treatment, its mechanisms might relate with calcium antagonism and attenuation of MMP-9 expression in brain tissues.