Stop codon variant in EFEMP1 is associated with primary open-angle glaucoma due to impaired regulation of aqueous humor outflow.

It is known that the actin cytoskeleton and its associated cellular interactions in the trabecular meshwork (TM) and juxtacanalicular tissues mainly contribute to the formation of resistance to aqueous outflow of the eye. Fibulin-3, encoded by EFEMP1 gene, has a role in extracellular matrix (ECM) modulation, and interacts with enzymatic ECM regulators, but the effects of fibulin-3 on TM cells has not been explored. Here, we report a stop codon variant (c.T1480C, p.X494Q) of EFEMP1 that co-segregates with primary open angle glaucoma (POAG) in a Chinese pedigree. In the human TM cells, overexpression of wild-type fibulin-3 reduced intracellular actin stress fibers formation and the extracellular fibronectin levels by inhibiting Rho/ROCK signaling. TGFß1 up-regulated fibulin-3 protein levels in human TM cells by activating Rho/ROCK signaling. In rat eyes, overexpression of wild-type fibulin-3 decreased the intraocular pressure and the fibronectin expression of TM, however, overexpression of mutant fibulin-3 (c.T1480C, p.X494Q) showed opposite effects in cells and rat eyes. Taken together, the EFEMP1 variant may impair the regulatory capacity of fibulin-3 which has a role for modulating the cell contractile activity and ECM synthesis in TM cells, and in turn may maintain normal resistance of aqueous humor outflow. This study contributes to the understanding of the important role of fibulin-3 in TM pathophysiology and provides a new possible POAG therapeutic approach.

Evaluation of trabecular meshwork-specific promoters in vitro and in vivo using scAAV2 vectors expressing C3 transferase.

AIM: To evaluate the potential of two trabecular meshwork (TM)-specific promoters, Chitinase 3-like 1 (Ch3L1) and matrix gla protein (MGP), for improving specificity and safety in glaucoma gene therapy based on self-complementary AAV2 (scAAV2) vector technologies. METHODS: An scAAV2 vector with C3 transferase (C3) as the reporter gene (scAAV2-C3) was selected. The scAAV2-C3 vectors were driven by Ch3L1 (scAAV2-Ch3L1-C3), MGP (scAAV2-MGP-C3), enhanced MGP (scAAV2-eMGP-C3) and cytomegalovirus (scAAV2-CMV-C3), respectively. The cultured primary human TM cells were treated with each vector at different multiplicities of infections. Changes in cell morphology were observed by phase contrast microscopy. Actin stress fibers and Rho GTPases/Rho-associated protein kinase pathway-related molecules were assessed by immunofluorescence staining, real-time quantitative polymerase chain reaction and Western blot. Each vector was injected intracamerally into the one eye of each rat at low and high doses respectively. In vivo green fluorescence was visualized by a Micron III Retinal Imaging Microscope. Intraocular pressure (IOP) was monitored using a rebound tonometer. Ocular responses were evaluated by slit-lamp microscopy. Ocular histopathology analysis was examined by hematoxylin and eosin staining. RESULTS: In TM cell culture studies, the vector-mediated C3 expression induced morphologic changes, disruption of actin cytoskeleton and reduction of fibronectin expression in TM cells by inhibiting the Rho GTPases/Rho-associated protein kinase signaling pathway. At the same dose, these changes were significant in TM cells treated with scAAV2-CMV-C3 or scAAV2-Ch3L1-C3, but not in cells treated with scAAV2-eMGP-C3 or scAAV2-MGP-C3. At low-injected dose, the IOP was significantly decreased in the scAAV2-Ch3L1-C3-injected eyes but not in scAAV2-MGP-C3-injected and scAAV2-eMGP-C3-injected eyes. At high-injected dose, significant IOP reduction was observed in the scAAV2-eMGP-C3-injected eyes but not in scAAV2-MGP-C3-injected eyes. Similar to scAAV2-CMV-C3, scAAV2-Ch3L1-C3 vector showed efficient transduction both in the TM and corneal endothelium. In anterior segment tissues of scAAV2-eMGP-C3-injected eyes, no obvious morphological changes were found except for the TM. Inflammation was absent. CONCLUSION: In scAAV2-transduced TM cells, the promoter-driven efficiency of Ch3L1 is close to that of cytomegalovirus, but obviously higher than that of MGP. In the anterior chamber of rat eye, the transgene expression pattern of scAAV2 vector is presumably affected by MGP promoter, but not by Ch3L1 promoter. These findings would provide a useful reference for improvement of specificity and safety in glaucoma gene therapy using scAAV2 vector.

Cortical thickness differences are associated with cellular component morphogenesis of astrocytes and excitatory neurons in nonsuicidal self-injuring youth.

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.

Selective corticocortical connectivity suppression during propofol-induced anesthesia in healthy volunteers.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-021-09775-x.

Structural brain characteristics and gene co-expression analysis: A study with outcome label from normal cognition to mild cognitive impairment.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: Our results provide a theoretical foundation based on gene expression and brain imaging for the factors of NC with different outcomes.

Polymorphism rs11200638 enhanced HtrA1 responsiveness and expression are associated with age-related macular degeneration.

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 < 0.05). In ARPE-19 cells, HtrA1 promoters (-1 to -2175 bp from translation starting point) with risk allele A or normal G at rs11200638 did not show statistically significant differences in their luciferase reporter expression (p = 0.054425173), however, both promoters showed a persistent trend of higher luciferase expressions after 100 ng/ml LPS treatment. The luciferase expression level was significantly greater in the promoter with risk A when compared to that with normal G. Overexpression of HtrA1 resulted in apoptosis of ARPE-19 cells with 53.8 ± 1.6% of proliferation inhibition (p < 0.01). CONCLUSIONS: Risk 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.

Cortical Thickness Differences Are Associated With Chemical Synaptic Transmission Upregulated Genes in Degeneration of Mild Cognitive Impairment.

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.

Novel compound heterozygous mutations in CYP1B1 identified in a Chinese family with developmental glaucoma.

Developmental glaucoma, a subset of glaucoma, is associated with trabeculodysgenesis and/or anterior segment dysgenesis. It is one of the major causes of childhood blindness. Understanding its genetic background is important to diagnose, and identify potential therapeutic targets, of this disease. The present study aimed to detect the molecular origin of developmental glaucoma in a Chinese pedigree and its association with glaucomatous phenotypes. A three­generation pedigree with developmental glaucoma was analyzed in the current study; a thorough ocular examination was performed on the proband and other individuals in the family. Genomic DNA was extracted from the peripheral blood of each individual, and possible disease­causing genes were screened for mutations using a candidate gene panel. Exons and adjacent regions of the target genes were captured and enriched by probe hybridization. The enriched genes were sequenced on an Illumina high­throughput sequencer. Variations were verified in other family members using Sanger sequencing. Disease causing mutations were analyzed by comparing the sequences and the structures of wild­type and mutated cytochrome P450 family 1 subfamily B member 1 (CYP1B1) proteins using PyMOL software. The proband was diagnosed with developmental glaucoma and his parents and other relatives were asymptomatic. Novel compound heterozygous mutations, c.3G>A (p.M1I) and c.1310C>T (p.P437L), in CYP1B1 were detected in the proband, with the former inherited from his father and the latter from his mother. The c.3G>A (p.M1I) change is a novel mutation that disrupts the ATG start codon in exon one of CYP1B1 and therefore interferes with the translation start site. In conclusion, the findings of the present study suggested that the aforementioned compound heterozygous mutations in CYP1B1 may have caused developmental glaucoma in this Chinese family. The c.3G>A mutation in CYP1B1 is a novel mutation, and this study expands the gene mutation spectrum of CYP1B1.

A mutated CRYGD associated with congenital coralliform cataracts in two Chinese pedigrees.

AIM: To investigate the causal gene mutation and clinical characteristics for two Chinese families with autosomal dominant congenital coralliform cataract. METHODS: Two Chinese pedigrees with congenital cataract were investigated. Routine ophthalmic examinations were performed on all patients and non-affected family members. Peripheral blood samples were collected, and the genomic DNAs were extracted. The coding regions of proband's DNAs were analyzed with cataract gene panel. The identified mutation was amplified by polymerase chain reaction, and automated sequencing was performed in other members of two families to verify whether the mutated gene was co-segregated with the disease. RESULTS: Congenital coralliform cataract was inherited in an autosomal dominant mode in both pedigrees. For each family, more than half of the family members were affected. All patients presented with severe visual impairment after birth as a result of bilateral symmetric coralliform lens opacification. An exact the same defect in the same gene, a heterozygous mutation of c.70C>A (p. P24T) in exon 2 of γD-crystallin gene, was detected in both probands from each family. Sanger sequencing analysis demonstrated that the mutated CRYGD was co-segregated in these two families. CONCLUSION: A c.70C>A (p. P24T) variant in CRYGD gene was reconfirmed to be the causal gene in two Chinese pedigrees. It is known that mutated CRYGD caused most of the congenital coralliform cataracts, suggesting that the CRYGD gene is associated with coralliform congenital cataract.

Association between structural brain features and gene expression by weighted gene co-expression network analysis in conversion from MCI to AD.

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.

Asymmetrical alterations of grey matter among psychiatric disorders: A systematic analysis by voxel-based activation likelihood estimation.

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.

Differences in Brain Structural Covariance Network Characteristics in Children and Adults With Autism Spectrum Disorder.

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.

Predicting the progression of mild cognitive impairment to Alzheimer's disease by longitudinal magnetic resonance imaging-based dictionary learning.

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.

Abnormalities of effective connectivity and white matter microstructure in the triple network in patients with schizophrenia.

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.

Association of rs1059004 polymorphism in the OLIG2 locus with functional brain network in first-episode negative schizophrenia.

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.

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia.

OBJECTIVES: The frontal-striatum-thalamus pathway is important in the glutamic neural circuit. The hypofunction of GRIN1 and GRIA2 subunits from glutamic receptors has been hypothesized as the primary process in the etiology of schizophrenia. Identified gene polymorphism involved in the pathogenesis of schizophrenia may uncover relevant mechanism pathways. METHODS: We selected two loci of rs11146020 and rs3813296 distributed in GRIN1 and GRIA2 genes and tested their main and interaction effects on causality connections and structural characteristics in the frontal-striatum-thalamus pathway in 55 Han Chinese first-episode negative schizophrenia patients. RESULTS: We found that: (1) rs11146020 has a significant main effect on the causality connections between the bilateral dorsolateral prefrontal cortex, and rs3813296 mainly influences those of the descending pathway from the prefrontal cortex to the striatum; (2) interaction effect of rs11146020 and rs3813296 on causality connections are located in the ascending pathway from the pallidum to the dorsolateral prefrontal cortex; and (3) the two loci have effects on the volumes of several regions of this pathway. CONCLUSION: Our results suggested there is modulation on glutamic frontal-striatum-thalamus pathway by rs11146020 and rs3813296 gene polymorphism. Patients with different genotypes have different neuroimaging characteristics, which indirectly reminded clinicians those patients should receive different clinical interventions.

C3 Transferase-Expressing scAAV2 Transduces Ocular Anterior Segment Tissues and Lowers Intraocular Pressure in Mouse and Monkey.

Glaucoma is a lifelong disease with elevated intraocular pressure (IOP) as the main risk factor, and reduction of IOP remains the major treatment for this disease. However, current IOP-lowering therapies are far from being satisfactory. We have demonstrated that the lentivirus-mediated exoenzyme C3 transferase (C3) expression in rat and monkey eyes induced relatively long-term IOP reduction. We now show that intracameral injection of self-complementary AAV2 containing a C3 gene into mouse and monkey eyes resulted in morphological changes in trabecular meshwork and IOP reduction. The vector-transduced corneal endothelium and the C3 transgene expression, not vector itself, induced corneal edema as a result of actin-associated endothelial barrier disruption. There was a positive (quadratic) correlation between measured IOP and grade of corneal edema. This is the first report of using an AAV to transduce the trabecular meshwork of monkeys with a gene capable of altering cellular structure and physiology, indicating a potential gene therapy for glaucoma.

Effects of the 5-HT2A and DRD3 genotypes on cortical morphology and functional connectivity density in drug-naïve first episode schizophrenia.

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.

A multipredictor model to predict the conversion of mild cognitive impairment to Alzheimer's disease by using a predictive nomogram.

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 (Aß) concentration were selected by using Spearman correlation between the converted and not-converted patients. Then, a nomogram that combines image features, clinical factor, and Aß 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 Aß concentration as individual predictors. Significant associations were found between neuropsychological scores, cerebral cortex features, Aß 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, Aß levels, and underlying biological patterns from the macro- to the microperspective.

Genetic polymorphism in catechol-O-methyltransferase associated with the functional connectivity of frontostriatal circuits in first episode schizophrenia patients.

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.