Loss Of Outer Nuclear Layer Research Articles

Retina tissue validation of optical coherence tomography determined outer nuclear layer loss in FTLD-tau

Alzheimer’s disease (AD) is associated with inner retina (nerve fiber and ganglion cell layers) thinning. In contrast, we have seen outer retina thinning driven by photoreceptor outer nuclear layer (ONL) thinning with antemortem optical coherence tomography (OCT) among patients considered to have a frontotemporal degeneration tauopathy (FTLD-Tau). Our objective was to determine if postmortem retinal tissue from FTLD-Tau patients demonstrates ONL loss observed antemortem on OCT. Two probable FTLD-Tau patients that were deeply phenotyped by clinical and genetic testing were imaged with OCT and followed to autopsy. Postmortem brain and retinal tissue were evaluated by a neuropathologist and ocular pathologist, respectively, masked to diagnosis. OCT findings were correlated with retinal histology. The two patients had autopsy-confirmed FTLD-Tau neuropathology and had antemortem OCT measurements showing ONL thinning (66.9 μm, patient #1; 74.9 μm, patient #2) below the 95% confidence interval of normal limits (75.1–120.7 μm) in our healthy control cohort. Postmortem, retinal tissue from both patients demonstrated loss of nuclei in the ONL, matching ONL loss visualized on antemortem OCT. Nuclei counts from each area of ONL loss (2 – 3 nuclei per column) seen in patient eyes were below the 95% confidence interval (4 – 8 nuclei per column for ONL) of 3 normal control retinas analyzed at the same location. Our evaluation of retinal tissue from FTLD-Tau patients confirms ONL loss seen antemortem by OCT. Continued investigation of ONL thinning as a biomarker that may distinguish FTLD-Tau from other dementias is warranted.

Surgical Transplantation of Human RPE Stem Cell-Derived RPE Monolayers into Non-Human Primates with Immunosuppression.

SummaryRecent trials of retinal pigment epithelium (RPE) transplantation for the treatment of disorders such as age-related macular degeneration have been promising. However, limitations of existing strategies include the uncertain survival of RPE cells delivered by cell suspension and the inherent risk of uncontrolled cell proliferation in the vitreous cavity. Human RPE stem cell-derived RPE (hRPESC-RPE) transplantation can rescue vision in a rat model of retinal dystrophy and survive in the rabbit retina for at least 1 month. The present study placed hRPESC-RPE monolayers under the macula of a non-human primate model for 3 months. The transplant was able to recover in vivo and maintained healthy photoreceptors. Importantly, there was no evidence that subretinally transplanted monolayers underwent an epithelial-mesenchymal transition. Neither gliosis in adjacent retina nor epiretinal membranes were observed. These findings suggest that hRPESC-RPE monolayers are safe and may be a useful source for RPE cell replacement therapy.

Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration

In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, rd10. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised rd10 mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.

Blue Autofluorescence Fundus Imaging for Monitoring Retinal Degeneration in Royal College of Surgeons Rats.

PurposeDevelopment of a method for noninvasive longitudinal follow-up of retinal degeneration in the whole retina for Royal College of Surgeons (RCS) rats, a commonly used model of retinitis pigmentosa associated with mutations in the MER-proto-oncogene tyrosine kinase (MERTK) gene.MethodsPigmented RCS rats at postnatal (p) days p28 to p84 were subjected to a biweekly spectral-domain optical coherence tomography (SD-OCT), blue laser fundus autofluorescence (BL-FAF) imaging, and multicolor fundus imaging. Wild-type (WT; Long Evans) rats were tested as control.ResultsHyperautofluorescence developed throughout the fundus at p42, concomitant with a significant increase in SD-OCT thickness and reflectivity of the debris zone (DZ) layer as well as thinning of the photoreceptor outer nuclear layer (ONL). From p56 to p84, discrete hypofluorescent lesions surrounded by hyperfluorescent flecks were demonstrated around the optic disc that gradually spread throughout the retina. The hypofluorescent lesions were associated with loss of ONL and gradual thinning of the DZ layer. No hypofluorescent BL-FAF lesions were observed in WT rats.ConclusionsThis study suggests that BL-FAF imaging may present a new method for noninvasive longitudinal follow-up of retinal degeneration in nearly the whole retina in RCS rats.Translational RelevanceA clinical test was developed that may be implemented in translational studies in the RCS rat model of MERTK-associated retinitis pigmentosa.

Retinal pathology in the PPCD1 mouse.

Retinal phenotypes of the PPCD1 mouse, a mouse model of posterior polymorphous corneal dystrophy, have been characterized. PPCD1 mice on the DBA/2J background (D2.Ppcd1) have previously been reported to develop an enlarged anterior chamber due to epithelialization and proliferation of the corneal endothelium and subsequent blockage of the iridocorneal angle. Results presented here show that D2.Ppcd1 mice develop increased intraocular pressure (IOP), with measurements at three months of age revealing significant increases in IOP. Significant retinal ganglion cell layer cell loss is observed at five months of age. D2.Ppcd1 animals also exhibit marked degeneration of the outer nuclear layer in association with hyperplasia of the retinal pigment epithelium. Evidence of retinal detachment is present as early as three weeks of age. By 3.5 months of age, focal areas of outer nuclear layer loss are observed. Although the GpnmbR150X mutation leads to increased IOP and glaucoma in DBA/2J mice, development of anterior segment and retinal defects in D2.Ppcd1 animals does not depend upon presence of the GpnmbR150X mutation.

Systemic corticosteroids therapy in the management of acute zonal occult outer retinopathy.

Purpose. To report the efficacy of systemic steroid in treating acute zonal occult outer retinopathy (AZOOR). Methods. Retrospective study of 9 consecutive patients of AZOOR, who received systemic steroid therapy in Changhua Christian Hospital from 2005 to 2013, is presented. The duration of therapy was at least 3 months. Patients were evaluated with best corrected visual acuity (BCVA), optical coherence tomography (OCT), fluorescein angiography (FA), indocyanine green angiography (ICG), visual field test, and electroretinography (ERG). Results. At the initial visit, visual field defect was noted in all patients and impaired visual acuity was noted in 4 eyes. OCT examination revealed disrupted ellipsoid zone at the macular area in 8 eyes and outer nuclear layer (ONL) loss in 1 eye. At the end of follow-up, all patients had improvement of visual field. The 4 eyes with initial impaired visual acuity had BCVA recovering to 20/20. Follow-up OCT showed partial or complete recovery of the ellipsoid zone at the macular area in the 8 eyes with initial disrupted ellipsoid zone and stable condition in the eye with ONL loss. The mean follow-up duration was 47.11 ± 26.65 months. Conclusion. Visual improvement was achieved in most cases of recent onset AZOOR after systemic steroid treatment.

The Protective Effects of a Dietary Carotenoid, Astaxanthin, Against Light-Induced Retinal Damage

Dietary carotenoids exhibit various biological activities, including antioxidative activity. In particular, astaxanthin, a type of carotenoid, is well known as a powerful antioxidant. We investigated whether astaxanthin would protect against light-induced retinal damage. In an in vivo study, ddY male mice were exposed to white light at 8,000 lux for 3 h to induce retinal damage. Five days after light exposure, retinal damage was evaluated by measuring electroretinogram (ERG) amplitude and outer nuclear layer (ONL) thickness. Furthermore, expression of apoptotic cells, 8-hydroxy-deoxyguanosine (8-OHdG), was measured. In an in vitro study, retinal damage was induced by white light exposure at 2,500 lux for 24 h, and propidium iodide (PI)-positive cells was measured and intracellular reactive oxygen species (ROS) activity was examined. Astaxanthin at 100 mg/kg inhibited the retinal dysfunction in terms of ERG and ONL loss and reduced the expression of apoptotic and 8-OHdG-positive cells induced by light exposure. Furthermore, astaxanthin protected against increases of PI-positive cells and intracellular reactive oxygen species (ROS) activity in 661W cells. These findings suggest that astaxanthin has protective effects against light-induced retinal damage via the mechanism of its antioxidative effect.

Comparison of antifungal efficacies of moxifloxacin, liposomal amphotericin B, and combination treatment in experimental Candida albicans endophthalmitis in rabbits

The goal of this study was to compare in vitro and in vivo efficacy of moxifloxacin and liposomal amphotericin B (Amp-B) monotherapies and combination treatment against Candida albicans in an exogenous endophthalmitis model in rabbit eyes. Microplate dilution tests and checkerboard analysis were performed to detect in vitro efficacies. Endophthalmitis was induced by intravitreal injection of C. albicans in 40 rabbit eyes with simultaneous intravitreal drug injection according to prophylactic treatment groups. Group 1 (control group) received 0.1 mL of balanced salt solution, group 2 (moxi group) 100 microg moxifloxacin/0.1 mL, group 3 (Amp-B group) 10 microg liposomal Amp-B/0.1 mL, and group 4 (combi group) both 100 microg moxifloxacin/0.1 mL [DOSAGE ERROR CORRECTED] and 10 microg liposomal Amp-B/0.05 mL intravitreally. Clinical examination, quantitative analysis of microorganisms, and histopathologic examination were performed as in vivo studies. The minimum inhibitory concentration of liposomal Amp-B against C. albicans was found to be 1 microg/mL. Moxifloxacin showed no inhibition of in vitro C. albicans growth. The minimum inhibitory concentration values of liposomal Amp-B for C. albicans were reduced two- to eightfold with increasing concentrations of moxifloxacin in vitro. In vivo, there was no C. albicans growth in the combi group (zero of eight eyes), whereas three eyes (37.5%) showed growth in the Amp-B group. Vitreous inflammation, retinal detachment, focal retinal necrosis, and outer nuclear layer loss were found to be lower in the moxi group compared with the control group. Ganglion cell and inner nuclear layer loss was observed in all eyes (100%) in both the moxi and combi groups, whereas only in 25% (two of eight eyes) in the Amp-B group. Moxifloxacin strongly augments the efficacy of liposomal Amp-B against C. albicans in vitro, although it has no in vitro antifungal activity when used alone. It is interesting that we found a synergistic effect for in vitro tests but failed to demonstrate it in vivo. When 100 microg moxifloxacin/0.1 mL is given intravitreally, it has some toxic effects that are limited to the inner retinal layers.

Retinal Laminar Architecture in Human Retinitis Pigmentosa Caused byRhodopsinGene Mutations

To determine the underlying retinal micropathology in subclasses of autosomal dominant retinitis pigmentosa (ADRP) caused by rhodopsin (RHO) mutations. Patients with RHO-ADRP (n = 17, ages 6-73 years), representing class A (R135W and P347L) and class B (P23H, T58R, and G106R) functional phenotypes, were studied with optical coherence tomography (OCT), and colocalized visual thresholds were determined by dark- and light-adapted chromatic perimetry. Autofluorescence imaging was performed with near-infrared light. Retinal histology in hT17M-rhodopsin mice was compared with the human results. Class A patients had only cone-mediated vision. The outer nuclear layer (ONL) thinned with eccentricity and was not detectable within 3 to 4 mm of the fovea. Scotomatous extracentral retina showed loss of ONL, thickening of the inner retina, and demelanization of RPE. Class B patients had superior-inferior asymmetry in function and structure. The superior retina could have normal rod and cone vision, normal lamination (including ONL) and autofluorescence of the RPE melanin; laminopathy was found in the scotomas. With Fourier-domain-OCT, there was apparent inner nuclear layer (INL) thickening in regions with ONL thinning. Retinal regions without ONL had a thick hyporeflective layer that was continuous with the INL from neighboring regions with normal lamination. Transgenic mice had many of the laminar abnormalities found in patients. Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. The results in human class B and the transgenic mice support the following disease sequence: ONL diminution with INL thickening; amalgamation of residual ONL with the thickened INL; and progressive retinal remodeling with eventual thinning.

Inner Retinal Abnormalities in X-linked Retinitis Pigmentosa withRPGRMutations

To investigate in vivo the retinal microstructure in X-linked retinitis pigmentosa (XLRP) caused by RPGR mutations as a prelude to treatment initiatives for this common form of RP. Patients with RPGR-XLRP (n = 12; age range, 10-56 years) were studied by optical coherence tomography (OCT) in a wide region of central retina. Overall retinal thickness and outer nuclear layer (ONL) and inner retinal parameters across horizontal and vertical meridians were analyzed and compared. Retinal architecture of all patients with RPGR mutations was abnormal. At the fovea in younger patients, the ONL could be normal; but, at increasing eccentricities, there was a loss of photoreceptor laminar structure, even at the youngest ages studied. At later ages and advanced disease stages, the ONL was thin and reduced in extent. Inner retinal thickness, in contrast, was normal or hyperthick. Inner retinal thickening was detectable at all ages studied and was strongly associated with ONL loss. Inner retinal laminar abnormalities in RPGR-XLRP are likely to reflect a neuronal-glial retinal remodeling response to photoreceptor loss and are detectable relatively early in the disease course. These results should be factored into emerging therapeutic strategies for this form of RP.