Loss of aquaporin 9 expression adversely affects the survival of retinal ganglion cells.

Aquaporin 9 (AQP9), an aquaglyceroporin belonging to the AQP water channel family, is permeable not only to water but also to noncharged solutes such as lactate. In neurons, lactate presumably acts as an energy substrate and as a source of NADH (the reduced form of nicotinamide adenine dinucleotide), a scavenger of reactive oxygen species (ROS). We previously reported that retinal ganglion cells (RGCs) express AQP9 and that elevated intraocular pressure reduces AQP9 expression and increases death of neurons in the retinal ganglion cell layer of rodents. In the present study, we investigated the association of AQP9 expression with serum deprivation-induced death of RGC-5 cells and with death of neurons in the rat retinal ganglion cell layer after optic nerve transection (ONT). The effect of AQP9 RNA interference on serum deprivation-induced apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in RGC-5 cells was examined. Both serum deprivation and ONT significantly reduced AQP9 protein expression in RGCs and increased the rate of RGC death. Retinal AQP9 gene expression also declined after ONT. Down-regulation of AQP9 significantly increased apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in the RGC-5 cells. These findings suggest that AQP9 loss adversely affects survival of RGCs, at least partly because of decreased transport of lactate as a substrate for energy and/or ROS scavenger.

Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy.

PURPOSE: To investigate whether complement factor H (CFH) gene DNA variants are associated with central serous chorioretinopathy (CSCR). DESIGN: Cross-sectional study. PARTICIPANTS: A case-control group of 140 CSCR subjects and 2 different control groups: 934 population-based controls and 335 hospital-based controls. METHODS: Five single-nucleotide polymorphisms (SNPs) in CFH (rs3753394, rs800292, rs2284664, rs1329428, and rs106548) were evaluated for association with CSCR in 2 separate association analyses comparing CSCR subjects with 2 different control groups. Genotyping was performed using TaqMan technology (Applied Biosystems, Foster City, CA). MAIN OUTCOME MEASURES: Allele and haplotype frequencies of the 5 variants in the CFH region. RESULTS: Highly statistically significant associations with CSCR were found for the 5 SNPs. The strongest association was observed with rs1329428 (allelic P = 6.44×10(-6); odds ratio, 1.79; 95% confidence interval [CI], 1.39-2.31, cases vs. population-based controls), which accounted for 35.5% of the population-attributable fraction for CSCR. Consistent with the analysis, rs1329428 showed the strongest disease association (allelic P = 1.00×10(-5); odds ratio, 1.89; 95% CI, 1.42-2.50) in comparing cases with hospital-based controls. The second most strongly associated SNP, rs1065489, was correlated highly with the most strongly associated SNP, rs1329428 (r(2) = 0.77), and their effects could not be distinguished statistically from each other. A conditional logistic regression analysis revealed that the 2 highly correlated SNPs, rs1329428 and rs1065489, account for the association signals detected at the CFH locus. CONCLUSIONS: We identified a novel association between CSCR and common CFH polymorphisms. Our findings support the involvement of CFH in the pathogenesis of CSCR; exploration of the role of CFH could yield important insights into the biological mechanisms underlying CSCR. Our identification of common CFH variants as susceptibility elements for CSCR will open new avenues for research, leading to a better understanding of CSCR pathogenesis and ultimately to the development of improved therapeutic approaches.

Sera from patients with seropositive neuromyelitis optica spectral disorders caused the degeneration of rodent optic nerve.

Neuromyelitis optica (NMO) is an autoimmune inflammatory, neurodestructive disease primarily targeting the optic nerve and spinal cord. An autoantibody against water channel protein aquaporin-4 (AQP4), which is expressed at endofeet of astrocytes has been implicated in the pathogenesis of NMO. We evaluated the impact of sera of seropositive patients with NMO spectrum disorders (NMOSDs) on the rodent optic nerve and retina. Serum was obtained either from patients with seropositive NMOSD (AQP4+), seronegative patient with idiopathic optic neuritis (AQP4-), and healthy volunteers (control). Anti-AQP4 antibody in a serum was measured by a previously established cell-based assay. The patients' sera were applied on the optic nerve after de-sheathed. Immunohistochemistry showed that at 7 days after the treatment, the area of the optic nerve exposed to the AQP4+ sera lost expression of both AQP4 and glial fibrillary acidic protein. Also, Human-IgG immunoreactivity and marked invasion of inflammation cells were observed in the optic nerve treated with AQP4+ serum. Immnoreactivity of neurofilament was reduced at 14 days after the treatment, not 7 days. Real-time polymerase chain reaction revealed the reduced gene expression of neurofilament in retina from the eye that was exposed to the AQP4+ sera at 14 days. Retrograde fluorogold-labeling on the retinal flatmount disclosed the significantly reduced number of retinal ganglion cells when the AQP4+ sera were applied. The present model has demonstrated that the sera from patients with seropositive NMOSDs led to the regional astrocytic degeneration and inflammatory cell invasion in the optic nerve, resulting in the ultimate loss of RGCs and their axons at areas beyond the injury site.

The expression of syntaphilin is down-regulated in the optic nerve after axonal injury.

The impairment of mitochondrial function is an important pathogenic factor in glaucoma and other optic neuropathies in which retinal ganglion cell (RGC) death is the fundamental pathology. Syntaphilin was recently discovered as a docking protein that affects mitochondrial mobility. However, no reports have investigated the involvement of syntaphilin in the visual system. We investigated the expression of syntaphilin in the rat retina, optic nerve and brain. The expression of syntaphilin exhibited varying patterns in the visual system. Syntaphilin was expressed in retinal ganglion cells in the retina, in the cell bodies of neurons in the superior colliculus and was abundant in the astrocytes of rat optic nerves (similar to the findings that syntaphilin is expressed in human optic nerves). After optic nerve transection, which caused RGC death and axonal degeneration, quantitative real-time RT-PCR was used to assess changes in gene expression in the rat retina and optic nerve. Syntaphilin gene and protein expression in the optic nerve was downregulated 3 and 7 days after optic nerve transection. Our study suggests that syntaphilin expression in astrocytes at the optic nerve might be involved in axonal injury.

Predicting visual outcome following surgery for idiopathic macular holes.

Since Kelly and Wendel [Arch Ophthalmol 1991;109:654-659] first reported successfully treating macular holes (MHs) using pars plana vitrectomy in 1991, MH surgery has been constantly improved. For example, introducing the removal of the internal limiting membrane considerably increased the closure rate of MHs, and the advent of microincision vitrectomy surgery reduced surgical trauma and decreased patient discomfort after surgery. As modern MH surgery can achieve a higher anatomical success rate and alleviate patients' postoperative distress, postoperative visual outcomes have lately become the primary concern. Informing patients of the expected visual acuity and visual improvement before surgery is ideal, but predicting postoperative visual outcomes is difficult because a large number of factors are associated with them. In this paper, we review previous studies and provide accumulating evidence for the relationship between individual prognostic factors and visual outcomes after MH surgery.

Polypoidal choroidal vasculopathy: clinical features and genetic predisposition.

Polypoidal choroidal vasculopathy (PCV) is currently recognized as a phenotype of age-related macular degeneration (AMD). PCV is believed to be a type of choroidal neovascularization, although some cases of PCV show a distinct vascular abnormality of the choroidal vessels. PCV often shows several unique clinical manifestations which are apparently different from typical neovascular AMD (tAMD). In addition, the natural course and response to treatment are often different between tAMD and PCV. Moreover, recent genetic studies suggested a possible difference in the genetic susceptibility to disease between tAMD and PCV, as well as the existence of heterogeneity among PCV cases. In viewing the accumulation of knowledge about PCV, we have summarized the recent literature regarding PCV in this review article to improve the understanding of this clinical entity including possible susceptibility genes. We will also discuss the optimal treatment strategies for PCV in accordance with the results of recent clinical and genetic studies.

Evaluating dissociated optic nerve fiber layer appearance using en face layer imaging produced by optical coherence tomography.

PURPOSE: To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) appearance after pars plana vitrectomy (PPV). METHODS: We retrospectively reviewed 189 eyes that underwent PPV with internal limiting membrane removal and judged the presence/absence of an apparent DONFL based on en face layer images produced by spectral-domain optical coherence tomography (SD-OCT). RESULTS: An apparent DONFL was observed in 47 (24.9%) eyes. The incidence of an apparent DONFL was significantly higher in the macular hole (MH) group (76.5%) than in the non-MH group (epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others; 4.9%; p < 0.001). In the logistic regression analysis, surgical indication for MH was identified as the most significant DONFL risk factor (odds ratio 63.7; p = 1.05 × 10(-8)). CONCLUSION: Postoperative OCT en face layer imaging clarified that MH eyes are liable to have an apparent DONFL following PPV.

Spectral-domain optical coherence tomography detects optic atrophy due to optic tract syndrome.

BACKGROUND: Unilateral injury of the optic tract leads to asymmetrical optic atrophy in both eyes derived from the crossing of the nerve fibers at the chiasm. This report demonstrates unique imaging appearances of optic atrophy due to this uncommon condition detected by spectral-domain optical coherence tomography (SD-OCT). METHODS: Cirrus and RTVue measurements were performed in four cases of optic tract syndrome. Circumpapillary retinal nerve fiber layer (cpRNFL) thickness was obtained from both instruments and ganglion cell complex (GCC) integrity was obtained from RTVue. The presumable reduction rates of quadrant cpRNFL thickness were calculated from the published normative database and compared between eyes with temporal hemianopia and those with nasal hemianopia. RESULTS: Both devices showed significant reduction of cpRNFL thickness, but did not have statistical difference in the reduction rates at temporal or nasal quadrant cpRNFL between contralateral and ipsilateral eyes to the lesion. Color-coded maps helped to visualize the unique pattern of cpRNFL and GCC thinning. CONCLUSIONS: SD-OCT can be used as a diagnostic tool for the optic tract syndrome.

Effectiveness of intravitreal ranibizumab in exudative age-related macular degeneration (AMD): comparison between typical neovascular AMD and polypoidal choroidal vasculopathy over a 1 year follow-up.

BACKGROUND: The effects of intravitreal ranibizumab (IVR) against exudative age-related macular degeneration (AMD) may be different associated with the lesion phenotype. This study was conducted to compare the outcomes of IVR between two different phenotypes of exudative AMD: typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This is a retrospective cohort study of 54 eyes from 54 subfoveal exudative AMD patients (tAMD 24, PCV 30 eyes). Three consecutive IVR treatments (0.5 mg) were performed every month, followed by re-injections as needed. Change in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were then compared between the tAMD and PCV groups over 12 months of follow-up. RESULTS: The mean BCVA was significantly improved (-0.11 logMAR units) at month 3 after the initial IVR (p <0 .001, Wilcoxon signed-rank test), and was sustained up to 12 months in all AMD patients (p =0.02). In the subgroup analysis, the tAMD group showed a significant improvement in their mean BCVA (-0.06, -0.17, -0.15 and -0.16 logMAR units at 1, 3, 6 and 12 months, respectively), but there was only a slight but non-significant improvement in the PCV group. The improvement in the BCVA was significantly greater in the tAMD group than in the PCV group (p = 0.043, repeated measures ANOVA) over 12 months. Both phenotypes showed significant improvements in the CRT during 12 months after the initial IVR. CONCLUSIONS: IVR is an effective therapy for tAMD and PCV in the BCVA improvement in Japanese patients over 12 months of follow-up. The phenotype of tAMD showed a significantly better outcome with IVR than PCV in terms of BCVA improvement.

[New insights into the study of optic nerve diseases].

Optical coherence tomography (OCT) provides a new dimenstion in ophthalmology because it allows evaluation of the pathology in vivo, and provides information to assist the management of macular disease and glaucoma. It is necessary to differentiate the diagnosis of glaucoma from diseases of the optic nerve and of the visual pathway. This study evaluates the usefulness of OCT in detecting disorders of the optic nerve and visual pathway. In addition, the pathogenesis of glaucomatous optic neuropathy (GON), the most common optic neuropathy, was investigated by focusing on the dynamics of aquaporin. I. Evaluation of optic nerve and visual pathway disorders by optical coherence tomography. The swinging flashlight test is an easy, sensitive, objective test to detect relative afferent pupillary defects (RAPD). The number of RAPD detected by the swinging flashlight test was closely correlated with the ratio of retinal nerve fiber layer thickness (RNFLT) between the two eyes of 20 cases of unilateral optic atrophy. OCT could assess the amount of RAPD that reflected an asymmetrical functional disturbance of the optic nerves, as a structural difference. The time courses of RNFLT and ganglion cell complex (GCC) changes' were observed immediately following the time of injury in 4 cases of traumatic optic neuropathy. OCT revealed that both the RNFLT and GCC decreased rapidly from 2 weeks after the injury until 20 weeks later. The RNFLT decreased significantly in the horizontal direction in comparison to the perpendicular direction in 34 eyes from the cases of optic chiasm syndrome. This means that OCT could quantitatively detect the band atrophy of the optic disc in optic chiasm syndrome. Measuring the RNFLT showed a thinning of RNFLT in the perpendicular direction in comparison to the horizontal direction in ipsilateral eyes and thinning in the horizontal direction in comparison to the perpendicular direction in the contralateral eyes in optic tract syndrome. Measuring the GCC showed a thinning of the GCC in the temporal hemifield to the central fovea of the ipsilateral eyes, and thinning of the GCC in the nasal hemifield of the contralateral eyes. This means that OCT could detect the structural changes of hourglass atrophy in the ipsilateral eye and band atrophy in the contralateral eye at the optic disc as well as the homonymous hemianopia in the visual field. OCT was useful in evaluating the optic nerve and visual pathway disorders, but there were also some limitations. The thinning area of RNFLT measured by OPTVue and Cirrus were in entirely opposite directions in cases of optic chasm syndrome. The reason was attributed to the better performance of RTVue in measuring a thin RNFLT on the nasal side of the optic disc in comparison to Cirrus. The specific characteristics of the instruments should be considered when the results of OCT are evaluated. II. Dynamics of aquaporin in the optic nerve Aquaporin (AQP) is a membrane protein that forms a water channel to facilitate water crossing the plasma membrane. AQP-4 was originally thought to be expressed in the optic nerve, but it is expressed only in the retrobulbar medullated region of the optic nerve and the expression of AQPs in the optic disc has not been detected. This study investigated the expressions of AQPs in the optic nerve in rat, monkey and human. The results demonstrate that only AQP-9 was expressed at the unmedullated pre-lamina cribrosa and lamina cribrosa regions, and both AQP-4 and AQP-9 were expressed at the medullated retrobulbar region. Astrocytes were observed to express AQP-9, because AQP-9 immunoreactivity was identical to that of glial fibrillary acidic protein. Elevated intraocular pressure substantially reduced AQP-9 expression in the optic nerve, whereas expression of AQP-4 was not changed in rat eyes. The same phenomena were also observed in the monkey eye with ocular hypertension as well as human eye with glaucoma. AQP-9 is an aquaglyceroporin that allows solutes such as lactate rather than water to cross the cell membrane. The astrocyte-to-neuron lactate shuttle hypothesis has been proposed, in which lactate transported from astrocytes is used by neurons as an energy substrate. Reduction of AQP-9 expression in the optic nerve head under elevated intraocular pressures might be closely related to the pathogenesis of GON.

Positive association of CD36 gene variants with the visual outcome of photodynamic therapy in polypoidal choroidal vasculopathy.

PURPOSE: To clarify the association between cluster of differentiation 36 (CD36) gene polymorphisms and the response to photodynamic therapy (PDT) in polypoidal choroidal vasculopathy (PCV). METHODS: One hundred and thirty-seven patients with PCV were enrolled. The patients were treated with PDT and followed up for more than 6 months. Retreatments were performed every 3 months as needed based on findings from angiography. Patients who showed an improvement in their best-corrected visual acuity at 6 months post-PDT were classified as PDT responders, and the others were defined as non-responders. For the 73 responders and 64 non-responders, 19 single nucleotide polymorphisms (SNPs) across the CD36 region were genotyped using the TaqMan assay. We analyzed the association between these variants and the visual outcomes of PDT. RESULTS: The allelic frequencies of the SNPs rs3211851, rs3173798, and rs3211908 showed nominally significant differences between the PDT responders and non-responders. Genotype association analysis revealed a significant association of SNP rs3173798 with the visual outcome of PDT in a dominant model. The presence of the C allele in rs3173798 was significantly associated with a poor response to PDT after multivariate logistic regression analysis with clinical pre-PDT parameters. The mean best-corrected visual acuity in the group with the TT genotype of rs3173798 was significantly improved over 12 months of follow-up after the initial PDT. CONCLUSIONS: The coding variants in CD36 are possibly associated with the visual outcome of PDT in patients with PCV.

The association of CD36 variants with polypoidal choroidal vasculopathy compared to typical neovascular age-related macular degeneration.

PURPOSE: To clarify the association of cluster of differentiation 36 (CD36) variants with polypoidal choroidal vasculopathy (PCV) and compare them with those in typical neovascular age-related macular degeneration (tAMD). METHODS: We included 349 Japanese AMD patients (210 PCV, 139 tAMD) and 198 age-matched controls. Four tag single-nucleotide polymorphisms (SNPs)-rs10499862, rs3173798, rs3211883, and rs3173800-in the CD36 region were genotyped using the TaqMan assay. Allelic and genotypic frequencies of the SNPs were tested. RESULTS: Although none of the SNPs tested were associated with PCV, the allelic frequencies of rs3173798 and rs3173800 were significantly different between PCV and tAMD patients. Genotype association analysis demonstrated different associations of these two SNPs between PCV and tAMD in the genotype model. Haplotype analysis revealed that the association of the major haplotype (T-T-T-T) at four selected SNPs in CD36 differed significantly between PCV and tAMD patients. CONCLUSIONS: The CD36 region may be associated with the difference in genetic susceptibility for PCV and tAMD.

Better performance of RTVue than Cirrus spectral-domain optical coherence tomography in detecting band atrophy of the optic nerve.

BACKGROUND: To assess the agreement and diagnostic performance between retinal nerve fiber layer (RNFL) thickness measurements obtained using the Cirrus (Carl Zeiss Meditec) and RTVue (Optovue Inc.) devices for detection of band atrophy (BA) in patients with permanent temporal hemianopia. METHODS: In this retrospective study, 26 eyes with BA and 64 control eyes were enrolled. The Cirrus optic disc cube protocol and the RTVue optic nerve head map protocol were used. The Cirrus measurements were extracted and regrouped to be topographically matched with the RTVue measurements. Concordance correlation and 95 % limits of agreement were assessed. Areas under the receiver operating characteristic curves (AUC) and the Spearman's correlation coefficient between average Humphrey total deviation in the temporal hemifield and average RNFL thickness were calculated. RESULTS: RTVue measured consistently thicker values than Cirrus in controls, whereas in eyes with BA, nasal segment measurements from the RTVue were thinner than those obtained using the Cirrus. Each quadrant showed moderate to close agreement in controls, whereas in eyes with BA, the nasal and temporal quadrants exhibited poor agreement. The RTVue measurements demonstrated significantly higher AUCs for nasal segments just above (0.95) and below (0.96) the horizontal meridian than Cirrus measurements (0.80 and 0.66, respectively) and a significant correlation with visual field loss (r(s) = 0.46, P = 0.02 for RTVue vs. r(s) = 0.26, P = 0.22 for Cirrus). CONCLUSIONS: The RTVue RNFL thickness measurements in nasal sectors showed better diagnostic performance in detecting BA and higher correlations with temporal hemianopia than the Cirrus measurements.

The association of age-related maculopathy susceptibility 2 polymorphisms with phenotype in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To determine the association of age-related maculopathy susceptibility 2 (ARMS2) gene polymorphisms with the phenotype of typical neovascular age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV) and the effects of photodynamic therapy (PDT). METHODS: The single nucleotide polymorphisms at rs10490924 (A69S) in ARMS2 of 68 tAMD and 119 PCV patients who underwent PDT were genotyped using the TaqMan assay. The baseline best corrected visual acuity (BCVA) and lesion size were compared among the three genotypes at rs10490924. A multivariate regression analysis was performed to evaluate the influence of the baseline BCVA, greatest linear dimension (GLD), and lesion phenotype (tAMD or PCV) on the association of rs10490924 with the BCVA 12 months after the first PDT. RESULTS: The mean lesion size was significantly different among the GG, GT, and TT genotypes at rs10490924 in the PCV group, although no significant differences were detected in the tAMD group. PCV patients with a G allele had significantly better vision at 3 months after the initial PDT. tAMD patients with a TT genotype had significantly poorer vision at 12 months after the first PDT. In the multivariate regression analysis, the additive model of the G allele at rs10490924 was associated with a significantly better BCVA 12 months after the first PDT in tAMD and PCV patients. CONCLUSIONS: ARMS2 variants are likely associated with the phenotype and the effects of PDT in tAMD and PCV.

Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).

PURPOSE: To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. RESULTS: The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta-analysis. CONCLUSIONS: Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder.

Investigation of the association between SLC1A3 gene polymorphisms and normal tension glaucoma.

PURPOSE: To investigate whether the solute carrier family 1, member 3 (SLC1A3) gene, which encodes the glutamate aspartate transporter, is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: Two hundred and ninety-five Japanese patients with NTG and 518 Japanese healthy controls were recruited. Patients exhibiting comparatively early NTG onset were selected because early onset suggests that genetic factors may show stronger involvement. We genotyped 5 single-nucleotide polymorphisms (SNPs) in SLC1A3 and assessed the allelic and genotypic diversity among cases and controls. RESULTS: There were no statistically significant differences in the frequency of SLC1A3 alleles and genotypes between cases and controls. CONCLUSIONS: Our study showed no association between SLC1A3 and NTG, suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis.

Complement factor H Y402H variant and risk of age-related macular degeneration in Asians: a systematic review and meta-analysis.

PURPOSE: To investigate whether the Y402H variant in the complement factor H gene is associated with age-related macular degeneration (AMD) in Asian populations. DESIGN: Meta-analysis of previous publications. PARTICIPANTS: Case-control groups of subjects with AMD and controls from 13 association studies. METHODS: We performed a meta-analysis of the association between Y402H and AMD in Asian populations using data available from 13 case-control studies involving 3973 subjects. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. The Q-statistic test was used to assess heterogeneity, and Egger's test was used to evaluate publication bias. Sensitivity analysis, cumulative meta-analysis, and meta-regression analysis were also performed. MAIN OUTCOME MEASURES: Allele and genotype frequencies of the Y402H variant. RESULTS: The Y402H variant showed a significant summary OR of 1.97 (95% CI, 1.54-2.52; P<0.001; allelic contrast model) per allele. Possession of at least 1 copy of the C allele increased the disease risk by 1.97-fold (95% CI, 1.63-2.39; P<0.001; dominant model) and accounted for 8.8% of the attributable risk of AMD in Asian populations. Sensitivity analysis indicated the robustness of our findings, and evidence of publication bias was not observed in our meta-analysis. Meta-regression analysis indicated no significant effect of baseline study characteristics on the summary effect size. Cumulative meta-analysis revealed that the summary ORs were stable and the 95% CIs narrowed with the accumulation of data over time. CONCLUSIONS: Our analysis provides substantial evidence that the Y402H variant is significantly associated with AMD in Asian populations. Our results expand the number of confirmed AMD susceptibility loci for Asians populations, which provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic tests by a combined evaluation of inherited susceptibility with previously established loci.

Diabetes induces expression of aquaporin-0 in the retinal nerve fibers of spontaneously diabetic Torii rats.

Diabetes redistributes the expression of glial aquaporin (AQP) water channels in the retina. However, it is not known whether diabetes also affects retinal AQP-0 expression. This study examined the effects of the development of diabetes on the expression of retinal AQP-0 in spontaneously diabetic Torii (SDT) rats. Male SDT rats at 10 and 40 weeks of age and age-matched male Sprague-Dawley (SD) rats were used. The localization of AQP-0 was assessed immunohistochemically using sagittal cryosections of the rats' retinas and optic nerves. Fold changes in AQP-0 gene expression relative to controls were assessed by real-time RT-PCR. All SDT rats spontaneously developed diabetes by 40 weeks of age (the mean hemoglobin (Hb) A1c levels were 2.8±0.2% and 11.2±1.0% at 10 and 40 weeks, respectively). SD rats did not develop diabetes (the HbA1c levels were 2.7±0.2% and 2.6±0.3% at 10 and 40 weeks, respectively). In the retinas of SD rats and in those of SDT rats at 10 weeks of age, immunoreactivity for AQP-0 was confined predominantly to the inner nuclear layer and to the border between the inner plexiform layer and the ganglion cell layer (GCL), where AQP-0 colocalized with protein kinase C-α. AQP-0 immunoreactivity was also observed in the GCL to a lesser degree, which colocalized with the neuronal nuclei. In the 40-week-old SDT rat retinas, additional AQP-0 immunoreactivity was observed in the GCL and colocalized with neurofilaments, indicating expression of AQP-0 in ganglion cell axons. However, the axonal AQP-0 immunoreactivity was restricted to the retinal nerve fibers, whereas the optic nerve axons were devoid of AQP-0. Retinal blood vessels did not express AQP-0. AQP-0 gene expression was 3.4-fold higher in SDT rat retinas than in SD rat retinas at 40 weeks of age. AQP-0 was predominantly expressed in the bipolar cells of the non-diabetic rat retinas, whereas it was also expressed in the retinal nerve fibers of diabetic rat retinas. The disrupted water transport between astrocytes and retinal nerve fibers may be associated with the known accelerated apoptosis of retinal ganglion cells induced by diabetes.

Receiver-operating characteristic analysis of multifocal VEPs to diagnose and quantify glaucomatous functional damage.

To test whether multifocal visual evoked potential (mfVEP) recording using two perpendicularly placed channels, as previously reported, to measure the degree of signal-to-noise ratio (SNR) distribution overlap between a signal window and a noise window would efficiently detect and quantify glaucomatous damage. Humphrey visual field (HVF) and mfVEP were recorded from 56 patients with primary open-angle glaucoma and mean deviation less than -15 dB and 62 age-matched ophthalmologically normal individuals. Areas under the receiver-operating characteristic curve (SNR-AUC) were calculated based on the proportion of mfVEP responses that exceeded a specific SNR criterion for both windows. Abnormal sectors with an SNR deviated from the previously established norm with P<5% and 1% were counted. Diagnostic accuracy of the SNR-AUC was similar to that of the average total deviation (TD) of the HVF. The hemifield agreement to detect a defect in mfVEP and HVF was 77.1-87.3%, which was similar to previous reports using multiple channels. Correlation coefficients between SNR-AUC and average TD (0.74 in the upper hemifield and 0.65 in the lower) were significantly higher than those between the sums of abnormal locations on the mfVEP and HVF probability plots (0.27 and 0.33, respectively). Two perpendicular channels can detect and quantify functional damage due to glaucoma. The SNR-AUC may be used as a global index to quantify diffuse glaucomatous functional loss.

Optimal conditions for multifocal VEP recording for normal Japanese population established by receiver operating characteristic analysis.

The purpose of this study was to establish optimal conditions for recording multifocal visual evoked potentials (mVEPs) in Japanese individuals, whose skull frame presumably differs from Caucasians. The scalp point that was extended from the calcarine fissure was identified using magnetic resonance imaging scans of 200 subjects. MVEPs were recorded from 56 individuals using three single channels and combinations of vertical and horizontal channels. Five electrodes were placed at the inion, 4 cm above the inion, 2.5 cm below the inion, 4 cm to the left or 4 cm to the right of the inion. The signal-to-noise ratio (SNR) was obtained by measuring the root-mean-square (RMS) amplitude of a signal window (45-150 ms) from each of 60-local responses that was divided by the average of the 60 RMS amplitudes of the noise window (325-430 ms). Receiver operating characteristic (ROC) analyses were performed based on the proportion of mVEP responses that exceeded a specific SNR criterion, calculated for both the signal window and the noise window. The position of the calcarine fissure relative to the inion was significantly lower than the value reported for Caucasians. The ROC analyses disclosed that bi-channel combinations (one vertical and one horizontal) had significantly better performance to discriminate signal from noise in 60-local mVEP responses compared to any single channel and performed similarly to the tri-channel combination. Two sets of perpendicular channels should be simultaneously used in recording mVEP responses from Japanese people, among whom skull frame characteristics differ from those observed in Caucasians.