Total Retinal Thickness Research Articles

Anatomical effects of intravitreal anti-vascular endothelial growth factor injections on inner layers of the lesion-free retina

Purpose The primary aim of the study was to investigate the effects of anti-vascular endothelial growth factor (VEGF) injections on the inner retinal layer anatomy of the lesion-free retina in eyes treated for neovascular age-related macular degeneration (nAMD). The secondary aim was to compare the changes of inner retinal layers in the lesion-free region of treated eyes with the same region of the untreated, fellow eyes and, thus, to elucidate any adverse effect of anti-VEGF treatments independently of 1-year aging changes. Methods This was a retrospective, longitudinal, case–control study of 50 eyes of 25 patients. Twenty-five eyes with nAMD comprised the study group (16 eyes treated with aflibercept and 9 eyes treated with ranibizumab) and 25 fellow eyes with dry AMD (16 eyes in AREDS 2 and 9 eyes in AREDS 3) comprised the fellow eye group. Spectral-domain optical coherence tomography (SD-OCT) measurements were done at pre-treatment, 1 month after three loading anti-VEGF injections and at the end of 1 year. The retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL) thicknesses and total retinal thickness in the macula were measured. Thicknesses of inner retinal layers which were lesion-free in the outer nasal subfield of ETDRS grid were analysed and the changes in thicknesses during the follow-up period were compared between study and fellow eye groups. Paired t-test for normally distributed variables was applied for analyses of differences for the comparison of the results across the pre-and the post-. A p value of less than 0.05 was considered statistically significant. Results The mean number of injections was 5.76 ± 1.26 in the study group in 1 year. The mean decrease in total retinal thickness was significant with 6.08 ± 9.05 µm (p= 0.003) in nAMD group and was insignificant with 0.32 ± 1.03 µm (p> 0.05) in fellow eye group with dry AMD. Most of the retinal thickness decrease was during first three injections in nAMD group. Total retinal thickness and GCL thickness were thinner in the study group at every follow-up examination, but the difference between groups was not statistically significant (p> 0.05). RNFL, GCL, IPL, and INL thicknesses did not demonstrate a statistically significant change in both study and fellow eye groups during 1 year follow-up period (p> 0.05). Conclusions Repeated anti-VEGF injections in nAMD appear to have no significant effect on the RNFL, GCL, IPL, and INL thicknesses of the lesion-free retina. Additionally, there was no significant difference in inner retinal layer changes between in eyes treated with anti-VEGF injections for nAMD and fellow eye group during 1-year follow-up.

Longitudinal normative OCT retinal thickness data for wild-type mice, and characterization of changes in the 3×Tg-AD mice model of Alzheimer's disease.

Mice are widely used as models for many diseases, including eye and neurodegenerative diseases. However, there is a lack of normative data for retinal thickness over time, especially at young ages. In this work, we present a normative thickness database from one to four-months-old, for nine layers/layer-aggregates, including the total retinal thickness, obtained from the segmentation of spectral-domain optical coherence tomography (SD-OCT) data from the C57BL6/129S mouse strain. Based on fifty-seven mice, this normative database provides an opportunity to study the ageing of control mice and characterise disease models' ageing, such as the triple transgenic mouse model of Alzheimer's disease (3×Tg-AD) used in this work. We report thickness measurements, the differences in thickness per layer, demonstrate a nasal-temporal asymmetry, and the variation of thickness as a function to the distance to the optic disc centre. Significant differences were found between the transgenic group's thickness and the normative database for the entire period covered in this study. Even though it is well accepted that retinal nerve fibre layer (RNFL) thinning is a hallmark of neurodegeneration, our results show a thicker RNFL-GCL (RNFL-Ganglion cell layer) aggregate for the 3×Tg-AD mice until four-months-old.

Foveal Differentiation and Inner Retinal Displacement Are Arrested in Extremely Premature Infants.

PurposeChildren with a history of prematurity often have poorly developed foveae but when during development foveal differences arise. We hypothesize that the course of foveal development is altered from the time of preterm birth.MethodsEyes of 102 preterm infants undergoing retinopathy of prematurity screening examinations in the STudy of Eye imaging in Premature infantS (BabySTEPS) (NCT02887157) were serially imaged between 30 and 42 weeks postmenstrual age (PMA) using handheld optical coherence tomography systems. Total retinal thickness, inner retinal layer (IRL) thickness, and outer retinal layer (ORL) thickness were measured at the foveal center and parafovea. Foveal put depth, IRL thickness, and ORL thickness were compared between infants born at different gestational ages using mixed effects models.ResultsFoveal pit depth and IRL thickness were inversely related to gestational age; on average, the most premature infants had the thickest IRL and shallowest pits at all PMAs. Differences were evident by 30 weeks PMA and persisted through 42 weeks PMA. The foveal pits of the most premature infants did not progressively deepen, and the IRLs did not continue to thin with increasing chronological age.ConclusionsFoveation in extremely preterm infants is arrested from the earliest observed ages and fails to progress through term equivalent age. The developmental displacement of the IRL from the foveal center into the parafovea does not occur normally after preterm birth. These observations suggest that foveal hypoplasia seen in children with history of prematurity is due to disturbances in foveal development that manifest within weeks of birth.

What Is Left After Resolution of Neonatal Retinal Hemorrhage: The Longitudinal Long-term Outcome in Foveal Structure and Visual Function

Neonatal retinal hemorrhage (NRH) is one of the most common neonatal fundus conditions. Hemorrhage resolves spontaneously; however, its long-term outcome is unknown yet. The current study explores the long-term role of NRH in foveal structure and visual function. Cohort study (a prospective longitudinal study, in which the participants were followed up for 4-6 years). A total of 125 healthy newborns during 2013-2015, including 50 newborns with NRH and 75 newborns without NRH, were enrolled. The eyes with NRH were further categorized into the foveal hemorrhage (FH) group and non-FH group. A comprehensive ophthalmic examination including best-corrected visual acuity (BCVA) measurement, slit-lamp examination, refractive error measurement, scanning laser ophthalmoscopy, and spectral-domain OCT was performed. Total retinal thickness (TRT) and the inner and outer retinal layers in the fovea were measured and compared. The NRH was absorbed within 2.1 ± 0.98 weeks (median: 3 weeks). No difference was noted in the demographic characteristics between the groups; there was no significant difference in the logMAR BCVA (P=.83) or in the TRT. Subgroup analysis showed that TRT at the fovea in the FH group was significantly thicker (P=.005). Segmentation analysis showed a significantly thicker foveal outer nuclear layer (ONL) in the FH group (P=.017). Birth-related retinal hemorrhage, even FH, might not lead to obvious visual abnormalities at the age of 4 years, at least according to this study with relatively small sample size. However, a thicker fovea, mainly attributed to a wider ONL and a shallower foveal pit, is noted in our study.

Assessment of inner retinal oxygen metrics and thickness in a mouse model of inherited retinal degeneration

The retinal degeneration 1 (rd1) mouse is a well-established model of inherited retinal degeneration, displaying photoreceptor degeneration and retinal vasculature damage. The purpose of the current study was to determine alterations in the rate of oxygen delivery from retinal circulation (DO2), the rate of oxygen extraction from the retinal circulation for metabolism (MO2), and oxygen extraction fraction (OEF) in rd1 mice. The study was performed in a total of 18 wild type (WT) and 10 rd1 mice at both 3-weeks and 12-weeks of age. Retinal arterial and venous oxygen contents (O2A and O2V) were measured using phosphorescence lifetime imaging. Total retinal blood flow (TRBF) was determined by fluorescence and red-free imaging. DO2 and MO2 were determined as TRBF × O2A and TRBF × (O2A-O2V), respectively. OEF was calculated as MO2/DO2. The thickness of individual retinal layers was measured from histology sections and inner retina (IR) and total retina (TR) thickness were calculated. TRBF, DO2 and MO2 were lower in rd1 mice compared to WT mice (P ≤ 0.001), whereas OEF was not significantly different between rd1 and WT mice (P = 0.4). TRBF and DO2 were lower at 3-weeks of age compared to 12-weeks of age (P ≤ 0.01), while MO2 was not significantly different between age groups (P = 0.4) and OEF was higher at 3-weeks of age compared to 12-weeks of age (P = 0.003). Additionally, the outer and inner retinal cell layer thicknesses were decreased in rd1 mice at 12-weeks of age compared to both age-matched WT mice and rd1 mice at 3-weeks of age (P ≤ 0.02). MO2 was directly correlated with both IR and TR thickness (R ≥ 0.50; P ≤ 0.03, N = 20). The findings indicate that the rate oxygen is supplied by the retinal circulation is decreased and the reduction in oxygen extracted for metabolism is related to retinal cell layer thinning in rd1 mice.

Effects of coconut water on blood sugar and retina of rats with diabetes.

BackgroundThis study aimed to evaluate the effects of coconut water on the general condition (fasting blood sugar and body weight) and retina of diabetic rats.MethodsForty-eight Sprague–Dawley male rats were divided into normal controls (NC), diabetes mellitus (DM), diabetes+coconut water (DM+CW), and diabetes+glibenclamide (DM+Gli) groups. After 4 weeks of normal feeding, coconut water was given to group III-DM+CW and 0.6 mg/kg glibenclamide to group IV–DM+Gli. The blood sugar, body weight, total retinal thickness, pathological changes, and VEGF expression in the retina were analyzed at different time points.ResultsThe fasting blood sugar was 4–6 mmol/L in group I-NC and continuously increased in group II-DM, whereas gradually decreased after the 4th experiment week in the remaining two groups. The rats, except in group I-NC, have lost weight. In group II-DM, the total retinal thickness was significantly increased after the 8th and 12th experiment week, and the pathological changes in retina were observed. VEGF was almost fully expressed in the ganglion cell layer and inner granular layer and partially expressed in the outer granular layer in group II-DM, and mainly expressed in the ganglion cell layer and inner layer in group I-NC, with a lighter color. Group III-DM + CW and group IV-DM + Gli demonstrated similar VEGF expression as in group I-NC.ConclusionsCoconut water has the potential to reduce blood sugar and diabetic retinal damage, serving as a candidate drug or nutrient for treating diabetes and its complications.

Microperimetry and Optical Coherence Tomography Changes in Type-1 Diabetes Mellitus without Retinopathy.

Background: We aimed to measure and correlate inner retinal layer (IRL) thickness and macular sensitivity by optical coherence tomography (OCT) and by microperimetry, respectively, in type 1 diabetes mellitus patients (DM1) without diabetic retinopathy (DR). Methods: Fifty-one DM1 patients and 81 age-matched healthy subjects underwent measurement of the axial length (AL), retinal thickness in the macular ETDRS areas by swept source (SS)-OCT and macular sensitivity by microperimeter. Results: The total retinal and IRL thicknesses were thicker in the DM1 group (p < 0.05) in practically all ETDRS areas, and they had a generalized decrease in sensitivity (p < 0.05) in 9 areas between both groups. There was a significant negative correlation between retinal sensitivity and age in all areas and in visual acuity (VA) in 5 out of the 9 areas for DM1 patients. Only a mild negative correlation was observed between retinal sensitivity in the 5° nasal inner (5NI) area and in IRL thickness in the temporal inner (TI) area (−0.309 with p = 0.029) in the DM1 group. Conclusion: Aging and disease evolution in DM1 patients without DR signs generate a decrease in retinal sensitivity. There was a direct relationship between retinal sensitivity and macular thickness in the DM1 group.

Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F.

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL−F/NL−F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals.Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve.Results: In the APPNL−F/NL−F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old.Conclusions: In the APPNL−F/NL−F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL−F/NL−F AD model may help us better understand the different retinal changes during the progression of AD.

An experimental pig model with outer retinal degeneration induced by temporary intravitreal loading of N-methyl-N-nitrosourea during vitrectomy

We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary experiment involving 5 mini-pig cases to determine the appropriate concentration of MNU, the vitreous cavity of each eye was filled with 4, 8, 10, 12, or 16 mg/mL MNU for 10 min, which was then replaced with a balanced salt solution. Multimodal examinations including spectral-domain optical coherence tomography (OCT) images and full-field electroretinography (ffERG) were obtained at baseline and week 2, week 6, and week 12. The retinal degeneration was classified according to the amplitudes of a dark adaptive (DA) 10.0 a-wave amplitude. The degree of moderate retinal degeneration was defined as DA 10.0 a-wave amplitude ≥ 10% and < 60% of baseline amplitude. The degree of severe degeneration was defined as DA 10.0 a-wave amplitude < 10% of baseline amplitude, noise, or flat signal. Hematoxylin and eosin staining and immunohistochemistry were performed at week 12. The main experiments were conducted first with 10 cases of 5 mg/mL and later with 13 cases of 10 mg/mL. In the preliminary experiment, degree of outer retinal degeneration increased with MNU concentration. Use of 4, 8, 10, 12, and 16 mg/mL MNU showed no, moderate, severe, severe, and atrophic changes, respectively. In the main experiments, there were 9 cases of moderate retinal degeneration and 1 case of severe degeneration in 5 mg/mL MNU group. Two cases of moderate degeneration and 11 of severe degeneration were recorded in 10 mg/mL group. Mean thickness of total retina, inner nuclear layer, and outer nuclear layer decreased at week 2 in both groups. The mean amplitudes on ffERG decreased at week 2. The ffERG and OCT findings did not change from week 2 to week 6 or week 12. The results of staining supported those of ffERG and OCT. Temporal MNU loading in a vitrectomized pig-eye model induced customized outer retinal degeneration with changing the concentration of MNU.

Retinal thickness changes over time in a AD mouse model (APPNL‐F/NL‐F) by SD‐OCT

PurposeAlzheimer' disease (AD) is a neurodegenerative brain pathology, characterized by a loss of neuron and their synapses. Similar changes have been found in the retina even before appeared in the brain. The retina has been postulated as an accessible biomarker of AD. The aim of this study was to analyze changes in retinal thickness over time in a mouse model of AD (APPNL‐F/NL‐F).MethodsRetinas of male APPNL‐F/NL‐F (n = 55) and WT (n = 39) animals were evaluated in vivo by SD‐OCT at 6, 9, 12, 15, 17 and 20 months old. The mean total retinal thickness was analysed following the ETDRS sectors. To analyse the RNFL, axonal ring scan around the optic nerve head was carried out. RNFL was measured in six sectors provided by the manufacturer. Only the left eyes were used to study.ResultsIn the APPNL‐F/NL‐F group compared to WT animals, the total retinal thickness showed a slight thinning up to the 15 months old, this being significant only at 6 months in the outer temporal ring. At 17 months, there was thickening in the total retinal thickness being significant in the inferior and nasal sectors, both in inner and outer rings. At 20 months, there was a significant thinning in superior and temporal retina, both in inner and outer rings. RNFL thickness showed similar changes, that being only significates, the thinning in the global analysis and in nasal and inner‐temporal sectors at 6 months old.ConclusionsIn the mouse model of AD (APPNL‐F/NL‐F), there is a thinning of the retinal thickness up to 15 months, followed by a thickening at 17 months and a subsequent thinning at 20 months in some retinal areas. These changes over time are similar to those observed in the human retina, with areas of thinning, possibly caused by neurodegeneration, followed by thickening, possibly caused by deposits and neuroinflammation; this experimental AD model could help for an extensive understanding of the different retinal changes during the AD progression.

Different Doses of β-Cryptoxanthin May Secure the Retina from Photooxidative Injury Resulted from Common LED Sources.

Retinal damage associated with loss of photoreceptors is a hallmark of eye diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Potent nutritional antioxidants were previously shown to abate the degenerative process in AMD. β-Cryptoxanthin (BCX) is an essential dietary carotenoid with antioxidant, anti-inflammatory, and provitamin A activity. It is a potential candidate for developing intervention strategies to delay the development/progression of AMD. In the current study, the effect of a novel, highly purified BCX oral formulation on the rat retinal damage model was evaluated. Rats were fed with BCX for four weeks at the doses of 2 and 4 mg/kg body weight in the form of highly bioavailable oil suspension, followed by retinal damage by exposing to the bright light-emitting diode (LED) light (750 lux) for 48 hrs. Animals were sacrificed after 48 hours, and eyes and blood samples were collected and analyzed. BCX supplementations (2 and 4 mg/kg) showed improvements in the visual condition as demonstrated by histopathology of the retina and measured parameters such as total retinal thickness and outer nuclear layer thickness. BCX supplementation helped reduce the burden of oxidative stress as seen by decreased serum and retinal tissue levels of malondialdehyde (MDA) and restored the antioxidant enzyme activities in BCX groups. Further, BCX supplementation modulated inflammatory markers (IL-1β, IL-6, and NF-κB), apoptotic proteins (Bax, Bcl-2, caspase 3), growth proteins and factors (GAP43, VEGF), glial and neuronal proteins (GFAP, NCAM), and heme oxygenase-1 (HO-1), along with the mitochondrial stress markers (ATF4, ATF6, Grp78, Grp94) in the rat retinal tissue. This study indicates that oral supplementation of BCX exerts a protective effect on light-induced retinal damage in the rats via reducing oxidative stress and inflammation, also protected against mitochondrial DNA damage and cellular death.

Optimal timing for activation of sigma 1 receptor in the Pde6brd10/J (rd10) mouse model of retinitis pigmentosa

Sigma 1 Receptor (Sig1R), a pluripotent modulator of cell survival, is a promising target for treatment of retinal degenerative diseases. Previously, we reported that administration of the high-affinity, high-specificity Sig1R ligand (+)-pentazocine, ((+)-PTZ) beginning at post-natal day 14 (P14) and continuing every other day improves visual acuity and delays loss of photoreceptor cells (PRCs) in the Pde6βrd10/J (rd10) mouse model of retinitis pigmentosa. Whether administration of (+)-PTZ, at time points concomitant with (P18) or following (P21, P24) onset of PRC death, would prove neuroprotective was investigated in this study. Rd10 mice were administered (+)-PTZ intraperitoneally [0.5 mg/kg], starting at either P14, P18, P21 or P24. Injections continued every other day through P42. Visual acuity was assessed using the optokinetic tracking response (OKR). Rd10 mice treated with (+)-PTZ beginning at P14 retained visual acuity for the duration of the study (~0.33 c/d at P21, ~0.38 c/d at P28, ~0.32 c/d at P35, ~0.32 c/d at P42), whereas mice injected beginning at P18, P21, P24 showed a decline in acuity when tested at P35 and P42. Their acuity was only slightly better than rd10-non-treated mice. Electrophysiologic function was assessed using scotopic and photopic electroretinography (ERG) to assess rod and cone function, respectively. Photopic a- and b-wave amplitudes were significantly greater in rd10 mice treated with (+)-PTZ beginning at P14 compared with non-treated mice and those in the later-onset (+)-PTZ injection groups. Retinal architecture was visualized in living mice using spectral domain-optical coherence tomography (SD-OCT) allowing measurement of the total retinal thickness, the inner retina and the outer retina (the area most affected in rd10 mice). The outer retina measured ~35 μm in rd10 mice treated with (+)-PTZ beginning at P14, which was significantly greater than mice in the later-onset (+)-PTZ injection groups (~25 μm) and non-treated rd10 mice (~25 μm). Following the visual function studies performed in the living mice, eyes were harvested at P42 for histologic analysis. While the inner retina was largely intact in all (+)-PTZ-injection groups, there was a marked reduction in the outer retina of non-treated rd10 mice (e.g. in the outer nuclear layer there were ~10 PRCs/100 μm retinal length). The rd10 mice treated with (+)-PTZ beginning at P14 had ~20 PRCs/100 μm retinal length, whereas the mice in groups beginning P18, P21 and P24 had ~16 PRCs/100 μm retinal length. In conclusion, the data indicate that delaying (+)-PTZ injection past the onset of PRC death in rd10 mice – even by a few days – can negatively impact the long-term preservation of retinal function. Our findings suggest that optimizing the administration of Sig1R ligands is critical for retinal neuroprotection.

Autoimmune retinopathy: findings and limitations from optical coherence tomography angiography

Background and objectiveTo report novel findings and limitations from optical coherence tomography angiography (OCTA) in the evaluation of autoimmune retinopathy (AIR).Study designWe retrospectively reviewed features of five patients diagnosed with AIR and five controls. OCTA scans were obtained and manually segmented to provide accurate measurements of foveal avascular zone (FAZ), vessel density, and retinal thickness at different levels.ResultsThe total retina and superficial vessel density throughout the whole scan were similar between AIR and controls (p = 0.14 and p = 0.11), whereas deep vessel density was decreased in AIR compared controls (p = 0.02). Decreased vessel density was most pronounced in the parafoveal and perifoveal areas (p = 0.01 and p = 0.01). AIR patients also had reduction of total retinal thickness in the perifoveal zone (p = 0.03), corresponding to outer retinal thinning (p = 0.001).ConclusionThis small series shows that AIR patients have reduced deep vessel density, particularly in the parafoveal and perifoveal regions and a decrease in macular thickness. These findings show correlation with the classic “flying saucer” sign seen on OCT.

Optic Nerve Head Morphological Changes Over 12 Hours in Seated and Head-Down Tilt Postures.

PurposeThe purpose of this study was to determine changes in optic nerve head (ONH) morphology in seated and 6° head-down tilt (HDT) postures over a 12-hour period.MethodsThirty eyes of 30 healthy human subjects (15 females) were included. Composite radial and circular optical coherence tomography (OCT) scans centered on the ONH, intraocular pressure (IOP), and optic nerve sheath diameter (ONSD) were acquired every two hours from 7 a.m. to 7 p.m. for both seated (n = 30) and HDT (n = 10) sessions. Global minimum rim width (BMO-MRW), total retinal thickness (TRT), retinal nerve fiber layer thickness (RNFLT), and Bruch's membrane opening (BMO) height were quantified.ResultsBMO-MRW decreased an average of 9.55 ± 8.03 µm (P < 0.01) over 12 hours in a seated position (range, −26.64 to +3.36 µm), and thinning was greater in females (−13.56 vs. −5.55 µm, P = 0.004). Modest decreases in TRT from the BMO to 500 µm (P < 0.04) and RNFLT for the 2.7, 3.5, and 4.2 mm circular scans (P < 0.02) were also observed. BMO-MRW thinning was not related to changes in IOP or ONSD (P = 0.34). In HDT, IOP and ONSD increased, BMO height moved anteriorly, and BMO-MRW thinning did not occur (P > 0.1).ConclusionsThe neuroretinal rim thins throughout the day in healthy individuals, and this change cannot be explained by changes in IOP or ONSD during the same time period. A HDT posture blunts the neuroretinal rim thinning observed in a seated position, suggesting a role of the translaminar pressure difference.

Photoreceptor Degeneration in Homozygous Male Per2luc Mice During Aging.

The Per2luc mouse model developed by Takahashi laboratory is one of the most powerful models to study circadian rhythms in real time. In this study, we report that photoreceptors degenerate in male Per2luc mice during aging. Young (2.5- to 5-month-old) and aged (11- to 13.5-month-old) homozygous male Per2luc mice and C57BL/6J mice were used for this study. Retina structure and function were investigated via spectral domain optical coherence tomography (SD-OCT), fundus imaging, and electroretinography (ERG). Zonula occludens-1 (ZO-1) immunofluorescence was used to analyze the retinal pigment epithelium (RPE) morphology. Fundus examination revealed no difference between young Per2luc and wild-type (WT) mice. However, the fundus of aged Per2luc mice showed white deposits, suggestive of age-related drusen-like formation or microglia, which were absent in age-matched WT mice. No differences in retinal structure and function were observed between young Per2luc and WT mice. However, with age, Per2luc mice showed a significant reduction in total retinal thickness with respect to C57BL/6J mice. The reduction was mostly confined to the photoreceptor layer. Consistent with these results, we observed a significant decrease in the amplitude of a- and b-waves of the ERG in aged Per2luc mice. Analysis of the RPE morphology revealed that in aged Per2luc mice there was an increase in compactness and eccentricity with a decrease in solidity with respect to the values observed in WT, pointing toward signs of aging in the RPE of Per2luc mice. Our data demonstrate that homozygous Per2luc mice show photoreceptor degeneration during aging and a premature aging of the RPE.

Longitudinal retinal layer changes in preclinical Alzheimer's disease.

PurposeSeveral studies found reduced retinal thickness on optical coherence tomography (OCT) in Alzheimer’s disease (AD), even in preclinical stages, labelling this technique of interest as biomarker. In this study, we examine retinal thickness changes in preclinical AD, as defined by cognitively normal individuals with amyloid‐beta (Aβ) on positron emission tomography (PET).MethodsFor this monocentre study, 145 cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the EMIF‐AD PreclinAD study. At baseline, participants underwent [18F] flutemetamol PET that was visually rated for cortical Aβ. Binding potential was calculated as continuous measure for Aβ. Optical coherence tomography (OCT) was performed at baseline and after 22 months to assess changes in total and individual inner retinal layer thickness in the macular region (ETDRS circles) and peripapillary retinal nerve fibre layer thickness. Differences in rate of change between amyloid‐beta positive and negative individuals and associations between binding potential and change in retinal thickness were evaluated.ResultsSixteen participants (11%) were positive for Aβ. Change in retinal thickness did not differ in any region between Aβ+ and Aβ− individuals. A positive association between binding potential and change in inner plexiform layer thickness was observed in the inner macular ring (beta = 1.708, CI = 0.575 to 2.841, p = 0.003).ConclusionAβ+ individuals did not differ in rate of change of any retinal layer compared to controls, but higher binding potential at baseline was associated with less IPL thinning over time. Optical coherence tomography (OCT) as a longitudinal screening tool for preclinical AD seems limited, but IPL changes offer leads for further research.

OCT Analysis in Patients with Relapsing-Remitting Multiple Sclerosis during Fingolimod Therapy: 2-Year Longitudinal Retrospective Study

Many studies have demonstrated the usefulness of some optical coherence tomography (OCT) parameters, like total macular volume (TMV) and retinal nerve fiber layer thickness (RNFL-T), for monitoring patients with multiple sclerosis (MS). However, there are no real-world, long-term studies on patients with relapsing-remitting MS (RR-MS) treated with fingolimod. Therefore, the purpose of this study was to describe retinal changes associated with fingolimod therapy during a two-year follow-up while considering previous episodes of optic neuritis (ON). Patients diagnosed with RR-MS and treated with fingolimod (46 in total) underwent a two-year follow-up. Based on previous ON history, we identified 16 ON+ and 30 ON− patients. The ophthalmological evaluations, including visual field (VF) examination and OCT, were performed at a baseline at 3–6, 12 and 24 months to evaluate the progression rate for each parameter. When analyzing the whole sample, OCT showed no cases of macular edema. Instead, we observed a significant reduction rate in the central retinal thickness (CRT) (p &lt; 0.001), TMV (p &lt; 0.001) and RNFL (p &lt; 0.05). Moreover, we observed a significant difference in the progression rate between ON+ and ON− patients, relative to the VF and RNFL (p &lt; 0.05) examinations. OCT highlighted a significant progression rate of retinal damage in MS patients despite fingolimod therapy, especially in MS ON+ patients.

High Correlation between Glaucoma Treatment with Topical Prostaglandin Analogs and BDNF Immunoreactivity in Human Retina

ABSTRACT Purpose To examine the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin-related kinase receptor-B (TrkB), in normal and glaucomatous human retinas. Methods Human retinas were collected from 8 donors who had been clinically diagnosed and treated for glaucoma, and from 9 control donors. Immunohistochemical analysis for BDNF and TrkB was performed. The percent of each retina expressing BDNF and TrkB was quantified for the total retinal thickness, and separately for the retinal ganglion cell (RGC) complex + retinal nerve fiber layer (RNFL). The expression of each protein was correlated with clinical outcomes obtained from the subject’s ocular histories. Results There was no significant difference in BDNF or TrkB expression when comparing glaucomatous and control retinas. Correlation analysis revealed a significant relationship between BDNF expression and the use of prostaglandin analogs. TrkB expression was highly correlated with the last-measured intraocular pressure (IOP), the use of carbonic anhydrase inhibitors, the use of beta blockers, and the total number of drugs used for the treatment of glaucoma. Conclusion Topical drugs used to treat glaucoma were associated with an increase in retinal BDNF and TrkB expression in human retina, independent of IOP, which may represent molecular evidence of neuroprotective pathway activation.

Matching Misaligned Spectralis OCTs to a Reference Scan in Pediatric Glaucoma with Poor Fixation and Nystagmus.

PurposePoor fixation or nystagmus in children causes misalignment errors when measuring circumpapillary retinal nerve fiber layer (cpRNFL) thickness by simultaneous scanning laser ophthalmoscope imaging/optical coherence tomography (SLO/OCT). We investigated a method to assess cpRNFL from misaligned SLO/OCT scans.MethodsHeidelberg Spectralis SLO/OCT scans from a single clinical examination were retrospectively analyzed when automated eye tracking was unreliable. Retinal layer thickness was measured at overlapping match locations between a reference and misaligned scans based on the position data from simultaneously acquired SLO images. Three layers were segmented: cpRNFL, internal limiting membrane to outer nuclear layer (ILM-ONL), and total retinal thickness (TR). Accuracy was defined as the difference in thickness between the reference and misaligned scans at their match locations after correction for scan angle.ResultsThirty-five subjects, evaluated for glaucomatous nerve loss, met inclusion criteria. Group-averaged accuracy was −2.7, 1.4, and 0.3 µm for cpRNFL, ILM-ONL, and TR thickness, respectively. Across all layers, interobserver intraclass correlation coefficients ranged from 0.97 to 0.63 and the maximum Bland-Altman 95% limits of agreement were −21.6 to 20.7 µm. Variability was greatest for cpRNFL thickness and least for TR thickness. Increased variability was associated with lower signal-to-noise ratio but not with image-motion indices of shear, rotation, and scale.ConclusionsRetinal layer thickness can be compared to a reference cpRNFL OCT scan when poor fixation and nystagmus causes misalignment errors. The analysis can be performed post hoc using multiple misaligned scans from standard SLO/OCT protocols.Translational RelevanceOur method allows for assessment of cpRNFL in children who fail eye tracking.

Utility of Spectral-Domain Optical Coherence Tomography in Differentiating Papilledema From Pseudopapilledema: A Prospective Longitudinal Study.

Prospective and longitudinal studies assessing the utility of spectral-domain optical coherence tomography (SD-OCT) to differentiate papilledema from pseudopapilledema are lacking. We studied the sensitivity and specificity of baseline and longitudinal changes in SD-OCT parameters with 3D segmentation software to distinguish between papilledema and pseudopapilledema in a cohort of patients referred for evaluation of undiagnosed optic disc elevation. Fifty-two adult patients with optic disc elevation were enrolled in a prospective longitudinal study. A diagnosis of papilledema was made when there was a change in the appearance of the optic disc elevation on fundus photographs as noted by an independent observer at or before 6 months. The degree of optic disc elevation was graded using the Frisen scale and patients with mild optic disc elevation (Frisen grades 1 and 2) were separately analyzed. SD-OCT parameters including peripapillary retinal nerve fiber layer (pRNFL), total retinal thickness (TRT), paracentral ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, and optic nerve head volume (ONHV) at baseline and within 6 months of follow-up were measured. Twenty-seven (52%) patients were diagnosed with papilledema and 25 (48%) with pseudopapilledema. Among patients with mild optic disc elevation (Frisen grades 1 and 2), baseline pRNFL (110.1 µm vs 151.3 µm) and change in pRNFL (ΔpRNFL) (7.3 µm vs 52.3 µm) were greater among those with papilledema. Baseline and absolute changes in TRT and ONHV were also significantly higher among patients with papilledema. The mean GCL-IPL thickness was similar at baseline, but there was a small reduction in GCL-IPL thickness among patients with papilledema. Receiver operator curves (ROCs) were generated; ΔpRNFL (0.93), ΔTRT (0.94), and ΔONHV (0.95) had the highest area under the curve (AUC). The mean baseline and absolute changes in SD-OCT measurements (pRFNL, TRT, and ONHV) were significantly greater among patients with papilledema, and remained significantly greater when patients with mild optic disc elevation were separately analyzed. ROCs demonstrated that ΔpRNFL, ΔTRT, and ΔONHV have the highest AUC and are best able to differentiate between papilledema and pseudopapilledema.