Binocular Interactions in Glaucoma Patients With Nonoverlapping Visual Field Defects:Contrast Summation, Rivalry, and Phase Combination

PURPOSE: In glaucoma, visual field defects in the left and right eye may be non-overlapping, resulting in an intact binocular visual field. In clinical management, these patients are often considered to have normal vision. However, visual performance also relies on binocular processing. The aim of this study was to evaluate binocular visual functions in glaucoma patients with intact binocular visual field, normal visual acuity, and stereoscopy. METHODS: We measured in 10 glaucoma patients and 12 age-similar controls: (1) monocular and binocular contrast sensitivity functions (CSF) using a modified quick CSF test to assess binocular contrast summation, (2) dominance during rivalry, and (3) contrast ratio at balance point with a binocular phase combination test. A mirror stereoscope was used to combine the left and right eye image (each 10° horizontally by 12° vertically) on a display. RESULTS: Area under the monocular and binocular CSF was lower in glaucoma compared to healthy (P < 0.001), but the binocular contrast summation ratio did not differ (P = 0.30). For rivalry, the percentage of time of mixed percept was 9% versus 18% (P = 0.056), the absolute difference of the percentage of time of dominance between the two eyes 19% versus 10% (P = 0.075), and the rivalry rate 8.2 versus 12.1 switches per minute (P = 0.017) for glaucoma and healthy, respectively. Median contrast ratio at balance point was 0.66 in glaucoma and 1.03 in controls (P = 0.011). CONCLUSIONS: Binocular visual information processing deficits can be found in glaucoma patients with intact binocular visual field, normal visual acuity, and stereoscopy

Retinal Contrast Gain Control and Temporal Modulation Sensitivity Across the Visual Field in Glaucoma at Photopic and Mesopic Light Conditions

PURPOSE. Glaucoma affects many aspects of visual performance, including adaptation, and this may depend on ambient luminance. We determine the influence of glaucoma and luminance on temporal aspects of adaptation, specifically on contrast gain control and temporal modulation sensitivity (TMS). METHODS. This case-control study included 12 glaucoma patients and 25 age-similar controls (50-70 years). Threshold perimetry was performed with a minimized testing grid (fovea and four peripheral locations). Stimuli (Goldmann size III 50 ms increment/decrement) were presented on a time-varying background with sinusoidally-modulated luminance (amplitude 60%; frequency 0-30 Hz; mean background luminance, 1 and 100 cd/m(2)). TMS (2.5-30 Hz) was measured in the same locations with a sinusoidally-modulated stimulus (Goldmann size IV, 334 ms) on a steady background (1 and 100 cd/m(2)). RESULTS. In healthy subjects, contrast sensitivity decreased with increasing background modulation frequency and increased again at very high frequencies, indicating contrast gain control. Minimum sensitivity was located between 2.5 and 20 Hz, depending on luminance and eccentricity. In glaucoma patients, the same frequency dependency was found (P = 0.12) but with an overall reduced sensitivity (P = 1 x 10(-5)), independent of luminance (P = 0.20). Decrements differentiated better between glaucoma and healthy subjects than increments (P = 0.004). TMS was reduced in glaucoma (P = 5 x 10(-6)) across all frequencies and luminance levels, with complete loss for high frequencies at 1 cd/m(2). CONCLUSIONS. Contrast gain control is largely unaffected in glaucoma, suggesting intact amacrine cell function. Perimetry with decrements or a high-frequency stimulus on a low-luminance background seems best to differentiate between glaucoma and healthy subjects

Three-dimensional structure of a mutant E.coli aspartate aminotransferase with increased enzymic activity

The aspartate and tyrosine aminotransferases from Escherichia coli have 43% sequence identity and nearly identical active sites. Both are equally good enzymes for dicarboxylate substrates, but the latter transaminates aromatic amino acids 1000 times faster. In an attempt to discover the critical residues for this differential substrate specificity, the aspartate aminotransferase mutant V39L has recently been prepared. It showed improved kcal/Km values for aspartate, glutamate and tyrosine and the corresponding oxo acids, mainly due to two to ten times lower Km values. For example, the Km values of V39L (wild type) for Asp and Glu are 0.12 (1.0) and 0.85 (2.7) mM respectively. The mutant was co-crystallized with 30 mM maleate from both polyethylene glycol and ammonium sulfate. Both structures were solved and refined to R-factors of 0.22 and 0.20 at 2.85 and 2.5 Å resolution respectively. They bear strong resemblance to the closed structure of the wild type enzyme complexed with maleate. The unexpected feature is that, for the first time, the closed form was produced in crystals grown from ammonium sulfate. It is concluded that the mutation has shifted the conformational equilibrium towards the closed form, which leads to generally reduced substrate Km

Microstructural Visual Pathway White Matter Alterations in Primary Open-Angle Glaucoma:A Neurite Orientation Dispersion and Density Imaging Study

BACKGROUND AND PURPOSE: DTI studies of patients with primary open-angle glaucoma have demonstrated that glaucomatous degeneration is not confined to the retina but involves the entire visual pathway. Due to the lack of direct biologic interpretation of DTI parameters, the structural nature of this degeneration is still poorly understood. We used neurite orientation dispersion and density imaging (NODDI) to characterize the microstructural changes in the pregeniculate optic tracts and the postgeniculate optic radiations of patients with primary open-angle glaucoma, to better understand the mechanisms underlying these changes.& nbsp;MATERIALS AND METHODS: T1- and multishell diffusion-weighted scans were obtained from 23 patients with primary open-angle glaucoma and 29 controls. NODDI parametric maps were produced from the diffusion-weighted scans, and probabilistic tractography was used to track the optic tracts and optic radiations. NODDI parameters were computed for the tracked pathways, and the measures were compared between both groups. The retinal nerve fiber layer thickness and visual field loss were assessed for the patients with glaucoma.& nbsp;RESULTS: The optic tracts of the patients with glaucoma showed a higher orientation dispersion index and a lower neurite density index compared with the controls (

Genome-wide CNV investigation suggests a role for cadherin, Wnt, and p53 pathways in primary open-angle glaucoma

BACKGROUND: To investigate whether copy number variations (CNVs) are implicated in molecular mechanisms underlying primary open-angle glaucoma (POAG), we used genotype data of POAG individuals and healthy controls from two case-control studies, AGS (n = 278) and GLGS-UGLI (n = 1292). PennCNV, QuantiSNP, and cnvPartition programs were used to detect CNV. Stringent quality controls at both sample and marker levels were applied. The identified CNVs were intersected in CNV region (CNVR). After, we performed burden analysis, CNV-genome-wide association analysis, gene set overrepresentation and pathway analysis. In addition, in human eye tissues we assessed the expression of the genes lying within significant CNVRs. RESULTS: We reported a statistically significant greater burden of CNVs in POAG cases compared to controls (p-value = 0,007). In common between the two cohorts, CNV-association analysis identified statistically significant CNVRs associated with POAG that span 11 genes (APC, BRCA2, COL3A1, HLA-DRB1, HLA-DRB5, HLA-DRB6, MFSD8, NIPBL, SCN1A, SDHB, and ZDHHC11). Functional annotation and pathway analysis suggested the involvement of cadherin, Wnt signalling, and p53 pathways. CONCLUSIONS: Our data suggest that CNVs may have a role in the susceptibility of POAG and they can reveal more information on the mechanism behind this disease. Additional genetic and functional studies are warranted to ascertain the contribution of CNVs in POAG. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-021-07846-1

Bioinformatic Prioritization and Functional Annotation of GWAS-Based Candidate Genes for Primary Open-Angle Glaucoma

BACKGROUND: Primary open-angle glaucoma (POAG) is the most prevalent glaucoma subtype, but its exact etiology is still unknown. In this study, we aimed to prioritize the most likely 'causal' genes and identify functional characteristics and underlying biological pathways of POAG candidate genes. METHODS: We used the results of a large POAG genome-wide association analysis study from GERA and UK Biobank cohorts. First, we performed systematic gene-prioritization analyses based on: (i) nearest genes; (ii) nonsynonymous single-nucleotide polymorphisms; (iii) co-regulation analysis; (iv) transcriptome-wide association studies; and (v) epigenomic data. Next, we performed functional enrichment analyses to find overrepresented functional pathways and tissues. RESULTS: We identified 142 prioritized genes, of which 64 were novel for POAG. BICC1, AFAP1, and ABCA1 were the most highly prioritized genes based on four or more lines of evidence. The most significant pathways were related to extracellular matrix turnover, transforming growth factor-β, blood vessel development, and retinoic acid receptor signaling. Ocular tissues such as sclera and trabecular meshwork showed enrichment in prioritized gene expression (&gt;1.5 fold). We found pleiotropy of POAG with intraocular pressure and optic-disc parameters, as well as genetic correlation with hypertension and diabetes-related eye disease. CONCLUSIONS: Our findings contribute to a better understanding of the molecular mechanisms underlying glaucoma pathogenesis and have prioritized many novel candidate genes for functional follow-up studies

An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development

Genetically complex ocular neuropathies, such as glaucoma, are a major cause of visual impairment worldwide. There is a growing need to generate suitable human representative in vitro and in vivo models, as there is no effective treatment available once damage has occured. Retinal organoids are increasingly being used for experimental gene therapy, stem cell replacement therapy and small molecule therapy. There are multiple protocols for the development of retinal organoids available, however, one potential drawback of the current methods is that the organoids can take between 6 weeks and 12 months on average to develop and mature, depending on the specific cell type wanted. Here, we describe and characterise a protocol focused on the generation of retinal ganglion cells within an accelerated four week timeframe without any external small molecules or growth factors. Subsequent long term cultures yield fully differentiated organoids displaying all major retinal cell types. RPE, Horizontal, Amacrine and Photoreceptors cells were generated using external factors to maintain lamination.</p

Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups

Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG. Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs. Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10(−05)), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1). Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma