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OBJECTIVES To investigate the role of polymorphism rs11200638 of high-temperature requirement factor A-1 (HtrA1) gene in the pathogenesis of age-related macular degeneration (AMD). METHODS Cultured adult retinal pigment epithelial cells (ARPE-19) expressing HtrA1 gene were treated with H2O2 or lipopolysaccharides (LPS) and analysed using western blot and quantitative polymerase chain reaction to illustrate the effects of oxidative and inflammatory stress on HtrA1 gene expression. Luciferase reporter plasmid driven by HtrA1 promoter with either normal allele G or risk allele A at SNP rs11200638 was transfected to ARPE-19 cells to investigate the effect of the G/A variation on HtrA1 promoter activity. The effects of HtrA1 overexpression on ARPE-19 cells were analysed with respect to percentage of cell proliferation inhibition and cell apoptosis. RESULTS HtrA1 expression was significantly increased with LPS or H2O2 stimulations (p

Systematically describing the structural topological configuration of human brain during development is an essential task. Autism spectrum disorder (ASD) represents a powerful challenge for psychiatry and neuroscience researchers. In this study, we investigated variations in the structural covariance network properties of 441 patients with ASD ranging in age from 7 to 45 years and in 426 age-matched healthy controls (HCs) using structural magnetic resonance neuroimaging from the ABIDE database. We applied a sliding window approach to study topological variation during development using comprehensive graph theoretical analysis. The main findings are as follows: (1) Cross-sectional trajectories of the network characteristics exhibited inverted U-shapes in both HCs and participants with ASD, with the latter exhibiting a 7-year delay in reaching the maximum value, (2) network resilience to targeted attacks peaked at 18' and 19' in the HCs and at 25' in the participants with ASD, and the weakest resilience occurred at age 7', (3) the HCs and participants with ASD exhibited normalized mean degree differences in the right amygdala, and (4) significant differences in the network characteristics were observed in the 18' age group at most of the densities analyzed. We used cross-sectional analysis to infer distinct neurodevelopmental trajectories in ASD in the brain structural connectome. Our findings are consistent with the notion that adolescence is a sensitive period of brain development with strong potential for brain plasticity, offering opportunities for environmental adaptation and social integration and for increasing vulnerability. ASD may be a product of susceptibility. LAY SUMMARY: We used cross-sectional analysis to preliminarily infer distinct neurodevelopmental trajectories in ASD in the brain structural connectome. The main findings are as follows: (1) Cross-sectional trajectories of the network characteristics exhibited inverted U-shapes in both HCs and participants with ASD, with the latter exhibiting a 7-year delay in reaching the maximum value, (2) Network resilience to targeted attacks peaked at 18' and 19' in the HCs and at 25' in the participants with ASD, and the weakest resilience occurred at age 7', (3) The HCs and participants with ASD exhibited normalized mean degree differences in the right amygdala, and (4) significant differences in the network characteristics were observed in the 18' age group at most of the densities analyzed.

Nonsuicidal self-injury (NSSI) generally occurs in youth and probably progresses to suicide. An examination of cortical thickness differences (ΔCT) between NSSI individuals and controls is crucial to investigate potential neurobiological correlates. Notably, ΔCT are influenced by specific genetic factors, and a large proportion of cortical thinning is associated with the expression of genes that overlap in astrocytes and pyramidal cells. However, in NSSI youth, the mechanisms underlying the relations between the genetic and cell type-specific transcriptional signatures to ΔCT are unclear. Here, we studied the genetic association of ΔCT in NSSI youth by performing a partial least-squares regression (PLSR) analysis of gene expression data and 3D-T1 brain images of 45 NSSI youth and 75 controls. We extracted the top-10 Gene Ontology terms for the enrichment results of upregulated PLS component 1 genes related to ΔCT to conduct the cell-type classification and enrichment analysis. Enrichment of cell type-specific genes shows that cellular component morphogenesis of astrocytes and excitatory neurons accounts for the observed NSSI-specific ΔCT. We validated the main results in independent datasets to verify the robustness and specificity. We concluded that the brain ΔCT is associated with cellular component morphogenesis of astrocytes and excitatory neurons in NSSI youth.

Mild cognitive impairment (MCI) is a transition between normal cognition (NC) and Alzheimer’s disease (AD). Differences in cortical thickness (ΔCT) have been reported in cases that degenerate from MCI to AD. The aspects of genetic and transcriptional variation related to ΔCT are vague. In this study, using an 8-year longitudinal follow-up outcome, we investigated the genetic correlates of ΔCT in MCI subjects with degeneration from MCI to AD (MCI_AD). We employed partial least squares regression (PLSR) on brain T1-weighted magnetic resonance imaging (MRI) images of 180 participants [143 stable MCI (MCI_S) participants and 37 MCI_AD participants] and brain gene expression data from the Allen Institute for Brain Science (AIBS) database to investigate genes associated with ΔCT. We found that upregulated PLS component 1 ΔCT-related genes were enriched in chemical synaptic transmission. To verify the robustness and specificity of the results, we conducted PLSR analysis invalidation and specificity datasets and performed weighted gene co-expression network analysis instead of PLSR for the above three datasets. We also used gene expression data in the brain prefrontal cortex from the Gene Expression Omnibus (GEO) database to indirectly validate the robustness and specificity of our results. We conclude that transcriptionally upregulated genes involved in chemical synaptic transmission are strongly related to global ΔCT in MCI patients who experience degeneration from MCI to AD.

The 5-hydroxytryptamine 2A receptor (5-HT2A) and dopamine D3 receptor (DRD3) have been extensively studied as promising candidate genes for schizophrenia. Magnetic resonance imaging studies have demonstrated that schizophrenia is associated with widespread structural and functional abnormalities in the brain. Serotonin and dopamine receptors play crucial roles in the development of the human cerebral cortex and brain activity. However, how the 5-HT2A and DRD3 genes impact brain structure and function in schizophrenia remains unknown. In the present study, we investigated the main effect of disease state and the interaction effect between disease state and genotype of these two genes on cortical volume, thickness, surface area and functional connectivity density (FCD) in fifty-five drug-naïve first episode schizophrenia patients and fifty-three healthy controls. We found that the differences in local FCD (lFCD) and global FCD (gFCD) between patients and healthy controls were predominantly located in brain hub regions. The significant interaction effects of disease state and 5-HT2A and DRD3 genes on brain structure and function were mainly located in the temporal cortex. Our findings may help to improve the understanding of the relationship between 5-HT2A and DRD3 genotypes and schizophrenia pathogenesis.

Negative symptoms in schizophrenia have been associated with functional changes in frontostriatal pathways. Dysregulation of the dopamine signal in frontostriatal pathways leads to the symptomology observed in schizophrenia. Although the catechol-O-methyltransferase (COMT) gene, one of the susceptibility genes for schizophrenia, has been associated with dopamine activities in prefrontal and striatal regions, it is still unclear whether the disease state and COMT val158 met genotype have an interaction effect on the functional connectivity of frontostriatal pathways. In this study, we evaluated the possible interactions between COMT val158 met variations and the disease state on the resting-state functional connectivity (RSFC) of frontostriatal pathways in fifty-one first episode schizophrenia (FES) patients (val/val: 29, met +: 22) with prominent negative symptoms and forty-eight healthy controls (val/val: 31, met +: 17). Regions of interest were defined by the result of a meta-analysis of frontostriatal pathways using the Neurosynth database. We found a significant genotype × disease interaction effect on the RSFC between the bilateral anterior cingulate (ACC) and right caudate, which overlapped with the main effect of the disease state. Behavioural regression analysis suggested that RSFC between the right ACC and right caudate correlated with the severity of SANS avolition-apathy scores in patients who were met carriers but not in patients who were val homozygous. Our findings suggest that the RSFC of frontostriatal pathways may differentially affected by an individual's COMT val158 met genotype.

Predicting the probability of converting from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) is still a challenging task. This study aims at providing a personalized MCI-to-AD conversion estimation by using a multipredictor nomogram that integrates neuroimaging features, cerebrospinal fluid (CSF) biomarker, and clinical assessments. To do so, 290 MCI patients were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 76 has converted to AD and 214 remained with MCI. All subjects were randomly divided into a primary and validation cohort. Radiomics signature (Rad-sig) was obtained based on 17 cerebral cortex features selected by using Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. Clinical factors and amyloid-beta peptide (Aβ) concentration were selected by using Spearman correlation between the converted and not-converted patients. Then, a nomogram that combines image features, clinical factor, and Aβ concentration was constructed and validated. Furthermore, we explored the associations between various predictors from the macro- to the microperspective by assessing gene expression patterns. Our results showed that the multipredictor nomogram (C-index 0.978 and 0.956 in both cohorts, respectively) outperformed the nomogram using either Rad-sig or Aβ concentration as individual predictors. Significant associations were found between neuropsychological scores, cerebral cortex features, Aβ levels, and underlying gene pathways. Our study may have a clinical impact as a powerful predictive tool for predicting the conversion probability of MCI and providing associations between cognitive impairment, structural changes, Aβ levels, and underlying biological patterns from the macro- to the microperspective.

Catechol-O-methyltransferase (COMT) gene variants have been reported to be implicated in the pathogenesis of psychotic symptoms in schizophrenia , especially in negative symptoms. These symptoms including apathy, blunted affect , social withdrawal and motor retardation. Neuroimaging studies suggested that negative symptoms appear to be associated with impaired activities of the prefrontal cortex in particular the dorsolateral prefrontal cortex (DLPFC). Given that the COMT gene is highly expressed in the DLPFC, it is poorly understood whether the disease state and COMT val 158met polymorphisms have main and interactive effect on the resting state functional connectivity (RSFC) of DLPFC-related pathways. To this end, fifty-five first episode schizophrenia (FES) and fifty-three healthy controls were genotyped using blood samples and underwent magnetic resonance imaging scanning. Seed-based voxel wise functional connectivity analysis was performed by placing bilateral pairs of seeds with DLPFC in area 46 defined by Brodmann's atlas. A two-ways ANCOVA model was performed with val158 met genotypes and disease state as the between subjects factors. Significant disease × COMT interactive effect was found mainly in the left DLPFC with the left anterior cingulate cortex, right precuneus , right superior parietal gyrus , which were overlapped with disease main effect. And these RSFC had positive correlations with affective blunting scores in FES patients with val homozygotes, but not with met carriers. Our results showed that the disease and the genotypes in COMT gene have significant interactive effect on RSFC of DLPFC and provided evidence for a disease-dependent pattern of gene action.

We comprehensively studied directional feedback and feedforward connectivity to explore potential connectivity changes that underlie propofol-induced deep sedation. We further investigated the corticocortical connectivity patterns within and between hemispheres. Sixty-channel electroencephalographic data were collected from 19 healthy volunteers in a resting wakefulness state and propofol-induced deep unconsciousness state defined by a bispectral index value of 40. A source analysis was employed to locate cortical activity. The Desikan-Killiany atlas was used to partition cortices, and directional functional connectivity was assessed by normalized symbolic transfer entropy between higher-order (prefrontal and frontal) and lower-order (auditory, sensorimotor and visual) cortices and between hot-spot frontal and parietal cortices. We found that propofol significantly suppressed feedforward connectivity from the left parietal to right frontal cortex and bidirectional connectivity between the left frontal and left parietal cortex, between the frontal and auditory cortex, and between the frontal and sensorimotor cortex. However, there were no significant changes in either feedforward or feedback connectivity between the prefrontal and all the lower-order cortices and between the frontal and visual cortices or in feedback connectivity from the frontal to parietal cortex. Propofol anesthetic selectively decreased the unidirectional interaction between higher-order frontoparietal cortices and bidirectional interactions between the higher-order frontal cortex and lower-order auditory and sensorimotor cortices, which indicated that both feedback and feedforward connectivity were suppressed under propofol-induced deep sedation. Our findings provide critical insights into the connectivity changes underlying the top-down mechanism of propofol anesthesia at deep sedation.The online version contains supplementary material available at 10.1007/s11571-021-09775-x.

To investigate the role of polymorphism rs11200638 of high-temperature requirement factor A-1 (HtrA1) gene in the pathogenesis of age-related macular degeneration (AMD).Cultured adult retinal pigment epithelial cells (ARPE-19) expressing HtrA1 gene were treated with HHtrA1 expression was significantly increased with LPS or HRisk haplotype A at rs11200638 significantly increased the responsiveness of HtrA1 promoter to inflammation and subsequently enhanced HtrA1 expression. HtrA1 overexpression induced ARPE-19 apoptosis and growth inhibition, relevant to pathogenesis of AMD.

Longitudinal studies reported that some elderly people with normal cognition (NC) converted to mild cognitive impairment (MCI), and some remained normal state (NC_S). The underlying factor for this difference conversion of NC is worthy of exploration METHODS: Eighty-three NC participants were tracked for eight years. Thirty participants transitioned from NC to MCI (NC_MCI). The remaining 53 participants retained an NC_S. The structural brain features and genetic expression of the 83 NC participants were obtained. We applied weighted gene co-expression network analysis (WGCNA) to inquire into the co-expression network of those. Mediator effect analysis of regulatory roles was conducted to inquire into the associations between brain measures, expression values, and clinical scores.The main results are: 1) 20 brain features and 740 gene expression had significant differences between the two groups, 2) one module including 187 genes had the most correlation with cortical thickness of left superior temporal sulcus (L.STS), 3) NFKBIA and RARA genes were the top two genes that made the greatest contribution to L.STS thickness, and 4) mediating effect was found between the L.STS thickness, the NFKBIA and RARA expression levels, and clinical scores.Our results provide a theoretical foundation based on gene expression and brain imaging for the factors of NC with different outcomes.

The aberrant orchestration between the triple networks has been suggested as a backbone for some cognitive and clinical features of schizophrenia. The salience network (SN) plays a general role in switching between the central executive network (CEN) and the default mode network (DMN) mediated by dopamine activity. Whether the disease state and dopamine associated gene, catechol-O-methyltransferase (COMT), has an interactive effect on the function and structure of the triple network has not been understood. To this end, independent component analysis was used to identify the triple network. Then, cortical thickness and inter-regional resting state functional connectivity (RSFC) of the triple network was investigated in 55 first episode schizophrenia (FES) patients and 53 age-, gender-, and education- matched healthy controls. Finally, we investigated if there exist interactive effect between disease and COMT gene variation on the abnormal brain structure and function. Our results show that patients with FES exhibited significantly increased RSFC between anterior cingulate cortex and left dorsolateral prefrontal cortex (DLPFC) compared with healthy controls. The cortical thickness of the left DLPFC was thinner in FES patients. Significant interaction effect between COMT and disease was found in cortical thickness of the left DLPFC. Specifically, cortical thinning in this region was evident with the val homozygotes group of the COMT gene in FES. This findings suggest abnormal RSFC between CEN and SN and thinker cortical thickness in FES. And the val homozygotes of COMT may contribute to further cortical thinning in FES patients.

Purpose: Mild cognitive impairment (MCI) is considered to be the clinical transition stage between patients with cognitively intact geriatrics and Alzheimer’s disease (AD). When observed longitudinally, however, a certain proportion of patients with MCI are expected to revert to a cognitively intact state (MCI_R) while others either remain in the MCI state (MCI_S) or deteriorate into AD (MCI_P). It is worthwhile to investigate the divergence in the brain activities of these MCI groups with different post hoc labels. Methods: In this study, we employed the regional homogeneity (ReHo) measure to explore the characteristics of local brain activity in these MCI groups. Results: Compared to age-matched normal controls, our results exhibited that (1) in MCI_R group, ReHo index showed an increase in the left insula and a decrease in the left superior temporal gyrus; (2) in MCI_S group, ReHo index increased in the left orbital part of the inferior frontal gyrus (IFG_orb) and decreased in the left inferior parietal lobe; and (3) in MCI_P group, ReHo index elevated in the left IFG_orb and decreased in the left putamen. Conclusions: The distinct ReHo changes in the individual MCI groups indicated a potential evidence for differentially active interventions for a specific patient with MCI.

Apolipoprotein E (APOE) ε4 allele is the genetic risk factor with the most established evidence for sporadic Alzheimer's disease. Previous neuroimaging studies have demonstrated insufficiently consistent functional and structural changes among healthy APOE ε4 carriers when compared to non-carriers. Here, in a cognitively intact elderly group (a total of 110: 45 APOE ε4 carriers, 65 non-carriers), we aimed to investigate the potential role of APOE ε4 in the modulation of grey matter activity, white matter integrity, and brain morphology before the development of clinically significant symptoms and signs, by methods of: amplitude of low frequency fluctuations and regional homogeneity analysis based on resting state fMRI, and fiber tractography approach based on diffusion tensor imaging. Our results revealed that compared to non-carriers, APOE ε4 carriers showed: (1) an inconsistent pattern of activity change in the default mode network, including increased gray matter activity in anterior cingulate cortex and medial prefrontal cortex and decreased activity in precuneus; (2) lower mean diffusivity (MD) in fibers of corona radiata and corpus callosum, and lower axial diffusivity in genu of corpus callosum; and (3) significant positive correlation between the MD value of the right superior corona radiate and gross white matter volume; significant negative correlation between the MD value of the right superior corona radiate and Mini-Mental State Examination (MMSE) score. Our results suggested that APOE ε4 gene can modulate gray matter activity and white matter integrity in cognitive and memory related regions, even before any clinical or neuropsychic symtoms or signs of imminent disease.

Objective Efficient prediction of the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) is important for the early intervention and management of AD. The aim of our study was to develop a longitudinal structural magnetic resonance imaging-based prediction system for MCI progression. Methods A total of 164 MCI patients with longitudinal data were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). After preprocessing, a discriminative dictionary learning framework was applied to differentiate MCI patches, avoiding the segmentation of regions of interest. Then, the proportion of patches classified as more severe atrophy patches in a patient was calculated as his or her feature to be input into a simple support vector machine. Finally, a new subject was predicted with fourfold cross-validation (CV), and the area under the receiver operating characteristic curve (AUC) was determined. Results The average accuracy and AUC values after fourfold CV were 0.973 and 0.984, respectively. The effects of the data from one or two time points were also investigated. Conclusion The proposed prediction system achieves desirable and reliable performance in predicting progression for MCI patients. Additionally, the prediction of MCI progression with longitudinal data was more effective and accurate. Significance The developed scheme is expected to advance the clinical research and treatment of MCI patients.

Disorganized communication among large-scale brain networks, especially in the salience network, default mode network and central executive network, have been consistently reported in schizophrenia (SZ) patients. However, abnormal patterns of the effective connectivity and abnormalities in the white matter of these networks remains unclear in patients with SZ. Fifty-six SZ patients and fifty-five healthy controls were enrolled in the present study and underwent resting state functional magnetic resonance and diffusion tensor imaging. Twelve main nodes within the triple networks were defined by independent components analysis. Effective connectivity between these main nodes was computed using Granger causality analysis. Voxel-based analysis of the diffusion tensor imaging data was conducted to explore white matter changes. The SZ patients showed abnormal effective connectivity between the anterior cingulate cortex and the dorsolateral prefrontal cortex. The abnormal white matter showed decreased fractional anisotropy localized in the bilateral anterior corona radiate and left superior long fasciculus in patients with SZ. These findings shed light on the importance of the triple network in the pathogenesis of SZ, which may facilitate the understanding of SZ.

Schizophrenia has often been viewed as a disorder of connectivity. The single nucleotide polymorphism rs1059004 in the oligodendrocyte lineage transcription factor 2 gene locus has been reported to be associated with schizophrenia. We measured the functional connectivity and functional brain network topology properties in 49 schizophrenic patients and 47 healthy controls. We compared the strength and diversity of the functional connectivity and topological properties of functional networks between different genotypes. The correlations among functional connectivity, topological properties and behavioral performances were also investigated in this study. We found that the connectivity strength of schizophrenic patients carrying the risk A allele was generally decreased whereas connectivity diversity was increased. Regarding topological properties, all groups showed small-world properties, the nodal efficiency showed significant differences in the right precuneus and left middle temporal pole between different genotypes in schizophrenic patients. Moreover, the nodal efficiency in the left middle temporal pole was positively correlated with the neuropsychological assessment battery results of the schizophrenic patients who were homozygous for the C allele. Our results elucidate the contribution of rs1059004 to the functional brain network, and may help enhance the present understanding of the role of risk gene in the functional dysconnectivity of schizophrenia.

Schizophrenia (SZ), bipolar disorder (BD) and major depression disorder (MDD) have been regarded as highly diverged independent entities in current psychiatric diagnosis. However, ample new evidence suggests that they may have common biological traits. Neuroimaging studies showed that psychiatric disorders might associated with altered grey matter (GM) asymmetry compared to controls; however, the degree to which SZ, BD and MDD have common and/or distinct asymmetrical alterations in GM is still ambiguous. In this study, we analysed 169 voxel-based studies (including 3517 SZ patients, 1575 BD patients, 3280 MDD patients and 9733 controls) using activation likelihood estimation (ALE) meta-analysis to systematically review the existence of similar GM atrophy and asymmetrical alteration patterns among these psychiatric disorders, and the functional association between behaviour domains and topological alterations. We found that the right parahippocampal gyrus and left superior frontal gyrus showed commonly altered GM volume across all three illnesses, but did not identify common asymmetrical alteration. The asymmetrical alteration with leftward bias appeared in SZ and bipolar disorder at different locations, but more asymmetrical alteration with rightward bias appeared in MDD. Moreover, these changes have been confirmed to be associate with several symptoms and may have roles in functional networks. Our findings support the existence of common neurobiological damnification in these psychiatric disorders and provides valuable insights for the neural commonalties among different psychiatric disorders based on a large sample size.

Alzheimer's disease (AD) is a neurodegenerative disease. Mild cognitive impairment (MCI) represents a state of cognitive function between normal cognition and dementia. Longitudinal studies showed that some MCI patients remained in a state of MCI, and some developed AD. The reason for these different conversions from MCI remains to be investigated. 180 MCI participants were followed for eight years. 143 MCI patients maintained the MCI state (MCI_S), and the remaining thirty-seven MCI patients were re-evaluated as having AD (MCI_AD). We obtained 1,036 structural brain characteristics and 15,481 gene expression values from the 180 MCI participants and applied weighted gene co-expression network analysis (WGCNA) to explore the relationship between structural brain features and gene expression. Regulating mediator effect analysis was employed to explore the relationships among gene expression, brain region measurements and clinical phenotypes. We found that 60 genes from the MCI_S group and 18 genes from the MCI_AD group respectively had the most significant correlations with left paracentral lobule and sulcus (L.PTS) and right subparietal sulcus (R.SubPS) thickness; CTCF, UQCR11 and WDR5B were the mutual genes between the two groups. The expression of CTCF gene and clinical score are completely mediated by L.PTS thickness, and the UQCR11 and WDR5B gene expression levels significantly regulate the mediating effect pathway. In conclusion, the factors affecting the different conversions from MCI are closely related to L.PTS thickness and the CTCF, UQCR11 and WDR5B gene expression levels. Our results add a theoretical foundation of imaging genetics for conversion from MCI to AD.

The rs1059004 in the oligodendrocyte lineage transcription factor 2 (OLIG2) gene has been reported to be a candidate single nucleotide polymorphism (SNP) for schizophrenia (SZ). A variety of functional magnetic resonance imaging (fMRI) studies have revealed disconnection in SZ. We aimed to investigate the association of rs1059004 polymorphism with whole-brain functional connectivity (FC) and to further explore the correlation between altered FC and cognitive behavioral scales. Fifty-five SZ patients and fifty-three matched healthy controls were included in this study. The general linear model was used to test the role of rs1059004 polymorphism in whole-brain FC based on resting-state fMRI. Spearman's rank correlation test was used to calculate the correlation coefficient between FC strength and behavior score. In the whole-brain FC analysis, we found that the FC pattern in SZ patients differs from healthy controls. Furthermore, compared to homozygous C carriers, risk A allele carriers have reduced FC strength in both SZ patients and healthy controls. For the correlation analysis in risk A allele carriers, we found a positive correlation between FC strength and verbal fluency score in SZ patients, while healthy controls appeared to have the opposite result. Our results revealed that participants carrying the risk A allele show FC patterns differing from those of homozygous C carriers. This result suggests that rs1059004 polymorphism and SZ have synergistic effects on brain connections. The correlation analysis result suggests that special attention should be paid to SZ patients who carry the risk A allele because the patients perform worse in verbal fluency.

The aberrant orchestration between the triple networks has been suggested as a backbone for some cognitive and clinical features of schizophrenia. The salience network (SN) plays a general role in switching between the central executive network (CEN) and the default mode network (DMN) mediated by dopamine activity. Whether the disease state and dopamine associated gene, catechol-O-methyltransferase (COMT), has an interactive effect on the function and structure of the triple network has not been understood. To this end, independent component analysis was used to identify the triple network. Then, cortical thickness and inter-regional resting state functional connectivity (RSFC) of the triple network was investigated in 55 first episode schizophrenia (FES) patients and 53 age-, gender-, and education- matched healthy controls. Finally, we investigated if there exist interactive effect between disease and COMT gene variation on the abnormal brain structure and function. Our results show that patients with FES exhibited significantly increased RSFC between anterior cingulate cortex and left dorsolateral prefrontal cortex (DLPFC) compared with healthy controls. The cortical thickness of the left DLPFC was thinner in FES patients. Significant interaction effect between COMT and disease was found in cortical thickness of the left DLPFC. Specifically, cortical thinning in this region was evident with the val homozygotes group of the COMT gene in FES. This findings suggest abnormal RSFC between CEN and SN and thinker cortical thickness in FES. And the val homozygotes of COMT may contribute to further cortical thinning in FES patients.

The aim of this study is to identify potential biomarkers that may distinguish people with Alzheimer’s disease (AD) from cognitively intact elderly. We analyzed the features of rich-club hierarchical network between the AD and a control group by diffusion tensor imaging. We detected that the changes between the two groups were located mainly in the feeder and local connections. Then, we calculated the betweenness centrality of the rich nodes and the strength values of all feeder connections, and we chose the nodes and connections that showed the most significant differences as features. We found that 1) Feeder and local connections were changed in the AD group; 2) Rich nodes of the left putamen and precuneus had significant differences in betweenness centrality between the AD and control groups; 3) Three connections showed significant differences. The obtained features were fed into a linear discriminant analysis for classifying AD from cognitively intact elderly. The classification accuracy is superior to that of traditional biomarkers (hippocampal volume and clinical scores). Our results suggested that rich-club hierarchical network analysis is a viable tool for finding potential biomarkers. The obtained features can be applied as potential biomarkers for distinguishing AD patients from cognitively intact elderly.

The aim of this work is to investigate the differences of effective connectivity of the default mode network (DMN) in Alzheimer's disease (AD) patients and normal controls (NC). The technique of independent component analysis (ICA) was applied to identify DMN components and multivariate Granger causality analysis (mGCA) was used to explore an effective connectivity pattern. We found that: (i) connections in AD were decreased than those in NC, in terms of intensity and quantity. Posterior cingulated cortex (PCC) exhibited significant activity in NC as it connected with most of the other regions within the DMN. Besides, the PCC was the convergence center which only received interactions from other regions; (ii) right inferior temporal cortex (rITC) in the NC exhibited stronger interactions with other regions within the DMN compared with AD patients; and (iii) interactions between medial prefrontal cortex (MPFC) and bilateral inferior parietal cortex (IPC) in the NC were weaker than those in AD patients. These findings may implicate a brain dysfunction in AD patients and reveal more pathophysiological characteristics of AD.

The rs6994992 polymorphism has been reported as a candidate variant associated with schizophrenia (SZ). Neuroimaging studies have revealed that SZ is associated with widespread structural and functional alterations in brain. However, whether the allele dosage of rs6994992 is associated with brain structural or functional features is unclear. We aimed to investigate the association between the risk allele dosage of rs6994992 and whole-brain structural and functional characteristics and to further explore the relationship between these characteristics and cognition. Magnetic resonance images and the rs6994992 genotype were obtained from 53 healthy participants. A general linear model was used to determine the effects of risk allele dosage of rs6994992 on brain characteristics. Spearman correlation analysis was employed to calculate the correlation between altered brain characteristics and cognitive scores. Our results demonstrated that regions with significant differences in structural characteristics between groups with different dosages of rs6994992 were mainly located in the frontal and temporal lobes, hippocampus and angular gyrus. Moreover, significant regions of functional connectivity (FC) partly overlapped with the structural results. Measurements in those significant regions and FCs were correlated with the cognition scales. This association can inform our understanding of the mechanisms through which rs6994992 variants increase the risk for SZ.

Objective Mild cognitive impairment (MCI) is often a transitional state between normal aging and Alzheimer's disease (AD). When observed longitudinally, some MCI patients convert to AD, while a considerable portion either remains MCI or revert to a normal functioning state. This divergence has provided some enlightenment on a potential biomarker to be represented in the resting state brain activities of MCI patients with different post-hoc labels. Recent studies have shown impaired executive functions, other than typically explicated memory impairment with AD/MCI patients. This observation raises the question that whether or not the executive control network (ECN) was impaired, which pivotally supports the central executive functions. Given the fact that effective connectivity is a sufficient index in detecting resting brain abnormalities in AD/MCI, the current study specifically asks a question whether the effective connectivity patterns are differentiated in MCI patients with different post-hoc labels. Methods We divided the MCI subjects into three groups depending on their progressive state obtained longitudinally: 1) 15 MCI-R subjects: MCI reverted to the normal functioning state and stabilized to the normal state in 24 months; 2) 35 MCI-S subjects: MCI patients maintained this disease in a stable state for 24 months; 3) 22 MCI-P subjects: MCI progressed to AD and stabilized to AD in 24 months, and 4) 39 age-matched normal control subjects (NC). We conducted a Granger causality analysis after identifying the core nodes of ECN in all of the subjects using Independent Component Analysis. Our findings revealed that different MCI groups presented different effective connectivity patterns within the ECN compared to the NC group. Specifically, (1) dorsolateral prefrontal cortex (dLPFC) and medial prefrontal cortex (mPFC) were the core nodes in the ECN network that exhibited different connecting patterns; (2) an effective connection circuit "R.dLPFC→ right caudate→ left thalamus→R.dLPFC" in the ECN showed different levels of damage; and (3) there were four pathways between the R.dLPFC and L.LP, and these four pathways were also different. Results Our results would help to understand the potential central mechanism of MCI patients. The differentiated effective connectivity of ECN may serve as a potential biomarker for early detection of AD, which may also provide a reference for clinical researchers to manipulate active but distinctive interventions for MCI patients who have different risks.

Amnestic mild cognitive impairment MCI (aMCI) has a high progression to Alzheimer's disease (AD). Recently, resting-state functional MRI (RS-fMRI) has been increasingly utilized in studying the pathogenesis of aMCI, especially in resting-state networks (RSNs). In the current study, we aimed to explore abnormal RSNs related to memory deficits in aMCI patients compared to the aged-matched healthy control group using RS-fMRI techniques. Firstly, we used ALFF (amplitude of low-frequency fluctuation) method to define the regions of interest (ROIs) which exhibited significant changes in aMCI compared with the control group. Then, we divided these ROIs into different networks in line with prior studies. The aim of this study is to explore the functional connectivity between these ROIs within networks and also to investigate the connectivity between networks. Comparing aMCI to the control group, our results showed that 1) the hippocampus (HIPP) had decreased FC with the medial prefrontal cortex (mPFC) and inferior parietal lobe (IPL), and the mPFC showed increased connectivity to IPL in the default mode network; 2) the thalamus showed decreased FC with the putamen and HIPP, and the HIPP showed increased connectivity to the putamen in the limbic system; 3) the supplementary motor area had decreased FC with the middle temporal gyrus and increased FC with the superior parietal lobe in the sensorimotor network; 4) increased connectivity between the lingual gyrus and middle occipital gyrus in the visual network; and 5) the DMN has reduced inter-network connectivities with the SMN and VN. These findings indicated that functional brain networks involved in cognition such as episodic memory, sensorimotor and visual cognition in aMCI were altered, and provided a new sight in understanding the important subtype of aMCI.

Gene delivery has potential for treating ocular disease and a number of delivery systems have been tested in animal models. However, several viral vectors have been shown to trigger undesirable transient inflammatory responses in the eye. Previously, it was shown that an attenuated Herpes simplex virus vector (hrR3) transduced numerous cell types in the anterior and posterior segments of monkey eyes, but this was accompanied by inflammation. In the retina, retinal pigment epithelial cells were the predominant cell type transduced by hrR3. IL-6 is an important pro-inflammatory cytokine and may play a role in the response to the hrR3 vector. Infection of human ARPE-19 cells with hrR3 resulted in increased IL-6 expression and secretion 3-4h post-infection. In the presence of acyclovir (70 microM) or in cells infected with UV-inactivated hrR3, IL-6 was not up-regulated indicating viral replication was required. Expression of the HSV-1 alpha and beta genes may be necessary but was not sufficient for NF-kappaB activation and IL-6 up-regulation. The translocation of NF-kappaB into the nucleus also occurred between 3 and 4h post-infection, coincident with increased IL-6 expression. Inhibition of NF-kappaB translocation by an Adenovirus vector expressing a dominant negative IkappaB (AdIkappaBam) inhibited IL-6 up-regulation, indicating that NF-kappaB plays a role in increasing IL-6 expression in APRE-19 cells. The hrR3 virus lacks viral ribonucleotide reductase (RR) activity, thus RR is not required for NF-kappaB activation or IL-6 up-regulation in ARPE-19 cells.

Visual cognition such as face recognition requires a high level of functional interaction between distributed regions of a network. It has been reported that the fusiform gyrus (FG) is an important brain area involved in facial cognition; altered connectivity of FG to some other regions may lead to a deficit in visual cognition especially face recognition. However, whether functional connectivity between the FG and other brain regions changes remains unclear during the resting state in amnestic mild cognitive impairment (aMCI) subjects. Here, we employed a resting state functional MRI (fMRI) to examine changes in functional connectivity of left/right FG comparing aMCI patients with age-matched control subjects. Forty-eight aMCI and thirty-eight control subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI) were analyzed. We focused on the correlation between low frequency fMRI signal fluctuations in the FG and those in all other brain regions. Compared to the control group, we found some discrepant regions in the aMCI group which presented increased or decreased connectivity with the left/right FG including the left precuneus, left lingual gyrus, right thalamus, supramarginal gyrus, left supplementary motor area, left inferior temporal gyrus, and left parahippocampus. More importantly, we also obtained that both left and right FG have increased functional connections with the left middle occipital gyrus (MOG) and right anterior cingulate gyrus (ACC) in aMCI patients. That was not a coincidence and might imply that the MOG and ACC also play a critical role in visual cognition, especially face recognition. These findings in a large part supported our hypothesis and provided a new insight in understanding the important subtype of MCI.

BACKGROUND AND PURPOSE:The intraocular pressure (IOP)-lowering and side effects in response to different prostaglandin F2α analogues can be variable, but, the underlying basis for this difference remains unknown. This study investigated the differential changes of cellular proteins relevant to IOP-lowering effects of latanoprost and bimatoprost. METHODS:The human T lymphoblast (MOLT-3) cell line and immortalized human trabecular meshwork (iHTM) cells were studied by quantitative PCR and by immunofluorescence after treatment with either latanoprost or bimatoprost. New Zealand white rabbit eyes were treated topically with each agent and, following euthanasia, anterior segment tissues were studied with immunostaining. RESULTS:In cultured MOLT-3 cells, mRNA expression of both c-fos and matrix metalloproteinase 9 increased significantly in response to each agent. In addition, there was little change in tissue inhibitor of metalloproteinase (TIMP)-3 mRNA, but a significant decrease in TIMP-4. Fibronectin mRNA in MOLT-3 cells was down-regulated with bimatoprost, but was up-regulated with latanoprost. Immunofluorescence analysis of iHTM cells showed that intracellular fibronectin was significantly decreased by bimatoprost, but was increased by latanoprost. Both latanoprost and bimatoprost increased mRNA expression of NF-кB p65 and decreased that of IкBα. Aquaporin-1 mRNA expression was significantly down-regulated by bimatoprost. Immunostaining also revealed a significant decrease of aquaporin-1 in the ciliary epithelium of New Zealand white rabbits after bimatoprost treatment. CONCLUSIONS:Similarities in protein expression produced by latanoprost and bimatoprost in vitro may be relevant to the mechanism for their IOP-lowering effects in vivo. Differences in fibronectin expression and in aquaporin-1 expression in response to each agent may contribute to variability in the IOP-lowering efficacy in some studies.

Drug-resistant bacterial infections and lack of available antibacterial agents in clinical practice are becoming serious risks to public health. We synthesized a new class of haloemodins by modifying a traditional Chinese medicine component, emodin. The novel haloemodin exerts strong inhibitory activity on bacterial topoisomerase I and DNA gyrase, and not on the topoisomerases of human origin. In principle, it shows remarkable antibacterial activities against laboratory and clinically isolated Gram-positive bacteria, including vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus. We further expanded its antibacterial spectrum into against Gram-negative bacteria with the assistance of polymyxin B nonapeptide, which helps haloemodin to penetrate through the bacterial outer membrane. Finally, the therapeutic effect of haloemodin in vivo was confirmed in curing S. aureus-induced keratitis on rabbit model. With distinctive structural difference from the antibiotics we used, the haloemodins are of value as promising antibacterial pharmacophore, especially for combat the infections caused by drug-resistant pathogens.

We used resting-state functional magnetic resonance imaging (fMRI) to investigate changes in the thalamus functional connectivity in early and late stages of amnestic mild cognitive impairment. Data of 25 late stages of amnestic mild cognitive impairment (LMCI) patients, 30 early stages of amnestic mild cognitive impairment (EMCI) patients and 30 well-matched healthy controls (HC) were analyzed from the Alzheimer's disease Neuroimaging Initiative (ADNI). We focused on the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. Compared to healthy controls, we found functional connectivity between the left/right thalamus and a set of brain areas was decreased in LMCI and/or EMCI including right fusiform gyrus (FG), left and right superior temporal gyrus, left medial frontal gyrus extending into supplementary motor area, right insula, left middle temporal gyrus (MTG) extending into middle occipital gyrus (MOG). We also observed increased functional connectivity between the left/right thalamus and several regions in LMCI and/or EMCI including left FG, right MOG, left and right precuneus, right MTG and left inferior temporal gyrus. In the direct comparison between the LMCI and EMCI groups, we obtained several brain regions showed thalamus-seeded functional connectivity differences such as the precentral gyrus, hippocampus, FG and MTG. Briefly, these brain regions mentioned above were mainly located in the thalamo-related networks including thalamo-hippocampus, thalamo-temporal, thalamo-visual, and thalamo-default mode network. The decreased functional connectivity of the thalamus might suggest reduced functional integrity of thalamo-related networks and increased functional connectivity indicated that aMCI patients could use additional brain resources to compensate for the loss of cognitive function. Our study provided a new sight to understand the two important states of aMCI and revealed resting-state fMRI is an appropriate method for exploring pathophysiological changes in aMCI.

Prostaglandin F(2)α analogs (PGAs), including latanoprost, travoprost and bimatoprost, the first choice for the pharmaceutical treatment of glaucoma, are gaining more attention on their systemic side effects in recent years. The gastro-intestinal effects are among the most reported adverse effects upon topical application of PGAs. Yet, the underlying mechanism remains to be unknown. In the current study, we performed a molecular genetic analysis on the patient reported by Yu et al. (BMJ Case Rep, 2009), who developed nausea, vomiting and diarrhea after topical application of travoprost and latanoprost, but not bimatoprost, and then speculated that the mechanism underlying the gastro-intestinal distress secondary to PGA topical application should be attributed to their stimulation of smooth muscles of the gastric and intestinal tract via prostanoid receptors. We postulate that the diversified receptor selectivity of various PGAs might mediate their diversified gastro-intestinal effects. To further verificate the speculation, other three glaucoma patients who exhibited different gastro-intestinal responses to different PGA medications were enrolled. The results suggested that the relative expression level of FP receptor, versus EP receptors, might be associated with the severity of gastro-intestinal effects incurred by PGAs. Owing to the differed expression levels of FP receptor, the responses of various patients to different PGAs can be variable.

PURPOSE We examined changes of the central nervous system in patients with advanced primary open-angle glaucoma (POAG). METHODS The clinical observational study included 15 patients with bilateral advanced POAG and 15 healthy normal control subjects, matched for age and sex with the study group. Retinal nerve fiber layer (RNFL) thickness was measured by optical coherence tomography (OCT). Using a 3-dimensional magnetization-prepared rapid gradient-echo sequence (3D-MP-RAGE) of magnetic resonance imaging (MRI) and optimized voxel-based morphometry (VBM), we measured the cross-sectional area of the optic nerve and optic chiasm, and the gray matter volume of the brain. RESULTS Patients in the POAG group compared to the subjects in the control group showed a significant (P < 0.001) decrease in the bilateral gray-matter volume in the lingual gyrus, calcarine gyrus, postcentral gyrus, superior frontal gyrus, inferior frontal gyrus, and rolandic operculum, as well as in the right cuneus, right inferior occipital gyrus, left paracentral lobule, and right supramarginal gyrus. Patients in the study group showed a significant increase in the bilateral gray matter volume in the middle temporal gyrus, inferior parietal gyrus, and angular gyrus, and in the left gray matter volume in the superior parietal gyrus, precuneus, and middle occipital gyrus. In addition, the cross-sectional area of the optic nerve and optic chiasm, and RNFL thickness were significantly decreased in the POAG group. CONCLUSIONS In patients with POAG, three-dimensional MRI revealed widespread abnormalities in the central nervous system beyond the visual cortex.