Retinal Neurodegeneration in Wilson’s Disease Revealed by Spectral Domain Optical Coherence Tomography

Background/Objective

In addition to cirrhosis of the liver, Wilson’s disease leads to copper accumulation and widespread degeneration of the nervous system. Delayed visual evoked potentials (VEPs) suggest changes to the visual system and potential structural changes of the retina.

Methods

We used the latest generation of spectral domain optical coherence tomography to assess the retinal morphology of 42 patients with Wilson’s disease and 76 age- and sex-matched controls. We measured peripapillary retinal nerve fiber layer (RNFL) thickness and total macular thickness and manually segmented all retinal layers in foveal scans of 42 patients with Wilson’s disease and 76 age- and sex-matched controls. The results were compared with VEPs and clinical parameters.

Results

The mean thickness of the RNFL, paramacular region, retinal ganglion cell/inner plexiform layer and inner nuclear layer was reduced in Wilson’s disease. VEPs were altered with delayed N75 and P100 latencies, but the N140 latency and amplitude was unchanged. An analysis of the laboratory parameters indicated that the serum concentrations of copper and caeruloplasmin positively correlated with the thickness of the outer plexiform layer and with N75 and P100 VEP latencies.

Conclusion

Neuronal degeneration in Wilson’s disease involves the retina and changes can be quantified by optical coherence tomography. While the VEPs and the thickness of the outer plexiform layer appear to reflect the current copper metabolism, the thicknesses of the RNFL, ganglion cell/inner plexiform layer, inner nuclear layer and the total paramacular thickness may be the best indicators of chronic neuronal degeneration.     

Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

BackgroundDiabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent.ObjectiveTo assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy.MethodsA literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software.ResultsThirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88μm, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21μm, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79μm, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99μm, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88μm, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22μm, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients.ConclusionPeripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention.     

Macular Thickness Measurements with Frequency Domain-OCT for Quantification of Retinal Neural Loss and its Correlation with Cognitive Impairment in Alzheimer?s Disease

PurposeTo evaluate the ability of frequency domain optical coherence tomography (fd-OCT) to estimate retinal neural loss in eyes with Alzheimer’s disease (AD). We also verified the existence of a correlation between AD-related cognitive impairment and macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements.Methodsfd-OCT scans were obtained from 45 eyes of 24 patients with AD and 48 control eyes. Peripapillary RNFL, macular full-thickness and segmented inner macular thickness parameters were calculated. The inner macular parameters included macular retinal nerve fiber layer (mRNFL) thickness, ganglion cell layer (GCL) plus inner plexiform layer thickness (GCL+), and RNFL plus GCL+ thickness (GCL++). The Mini-Mental State Examination (MMSE) was used to assess cognition in all subjects. The two groups were compared and the relationship between MMSE scores and fd-OCT measurements was verified.ResultsAverage, superior and inferior quadrant RNFL thickness parameters and all but one of the nine full-thickness macular measurements were significantly reduced in AD patients compared to controls. The segmented layers, GCL+ and GCL++ were significantly reduced in AD eyes. A significant correlation was found between most fd-OCT parameters (especially macular thickness measurements) and MMSE scores.ConclusionsMost fd-OCT peripapillary RNFL and macular full-thickness and segmented inner retinal layers parameters were reduced in AD eyes compared to controls. Moreover, neuronal loss, especially as reflected in macular parameters, correlated well with cognitive impairment in AD. Our results suggest that fd-OCT could be a potentially useful diagnostic tool in the evaluation and follow-up of AD patients.     

Relations between Cardiac and Visual Phenotypes in Diabetes: A Multivariate Approach

Cardiovascular disease and diabetes represent a major public health concern. The former is the most frequent cause of death and disability in patients with type 2 diabetes, where left ventricular dysfunction is highly prevalent. Moreover, diabetic retinopathy is becoming a dominant cause of visual impairment and blindness. The complex relation between cardiovascular disease and diabetic retinopathy as a function of ageing, obesity and hypertension remains to be clarified. Here, we investigated such relations in patients with diabetes type 2, in subjects with neither overt heart disease nor advanced proliferative diabetic retinopathy. We studied 47 patients and 50 controls, aged between 45 and 65 years, equally distributed according to gender. From the 36 measures regarding visual structure and function, and the 11 measures concerning left ventricle function, we performed data reduction to obtain eight new derived variables, seven of which related to the eye, adjusted for age, gender, body mass index and high blood pressure using both discriminant analysis (DA) and logistic regression (LR). We found moderate to strong correlation between left ventricle function and the eye constructs: minimum correlation was found for psychophysical motion thresholds (DA: 0.734; LR: 0.666), while the maximum correlation was achieved with structural volume density in the neural retina (DA: 0.786; LR: 0.788). Controlling the effect of pairwise correlated visual constructs, the parameters that were most correlated to left ventricle function were volume density in retina and thickness of the retinal nerve fiber layers (adjusted multiple R² is 0.819 and 0.730 for DA and LR), with additional contribution of psychophysical loss in achromatic contrast discrimination. We conclude that visual structural and functional changes in type 2 diabetes are related to heart dysfunction, when the effects of clinical, demographic and associated risk factors are taken into account, revealing a genuine relation between cardiac and retinal diabetic phenotypes.     

Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis

Background

Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are difficult to differentiate solely on clinical grounds. Optical coherence tomography (OCT) studies investigating retinal changes in both diseases focused primarily on the retinal nerve fiber layer (RNFL) while rare data are available on deeper intra-retinal layers.

Objective

To detect different patterns of intra-retinal layer alterations in patients with NMO spectrum disorders (NMOSD) and RRMS with focus on the influence of a previous optic neuritis (ON).

Methods

We applied spectral-domain OCT in eyes of NMOSD patients and compared them to matched RRMS patients and healthy controls (HC). Semi-automatic intra-retinal layer segmentation was used to quantify intra-retinal layer thicknesses. In a subgroup low contrast visual acuity (LCVA) was assessed.

Results

NMOSD-, MS- and HC-groups, each comprising 17 subjects, were included in analysis. RNFL thickness was more severely reduced in NMOSD compared to MS following ON. In MS-ON eyes, RNFL thinning showed a clear temporal preponderance, whereas in NMOSD-ON eyes RNFL was more evenly reduced, resulting in a significantly lower ratio of the nasal versus temporal RNFL thickness. In comparison to HC, ganglion cell layer thickness was stronger reduced in NMOSD-ON than in MS-ON, accompanied by a more severe impairment of LCVA. The inner nuclear layer and the outer retinal layers were thicker in NMOSD-ON patients compared to NMOSD without ON and HC eyes while these differences were primarily driven by microcystic macular edema.

Conclusion

Our study supports previous findings that ON in NMOSD leads to more pronounced retinal thinning and visual function impairment than in RRMS. The different retinal damage patterns in NMOSD versus RRMS support the current notion of distinct pathomechanisms of both conditions. However, OCT is still insufficient to help with the clinically relevant differentiation of both conditions in an individual patient.     

Retinal blood flow in diabetic retinopathy.

OBJECTIVES--(a) To report on the basic parameters of retinal blood flow in a population of diabetic patients with and without retinopathy and non-diabetic controls; (b) to formulate a haemodynamic model for the pathogenesis of diabetic retinopathy from this and other studies. DESIGN--Laser-Doppler velocimetry and computerised image analysis to determine retinal blood flow in a large cross sectional study. SETTING--Diabetic retinopathy outpatient clinic. SUBJECTS--24 non-diabetic controls and 76 diabetic subjects were studied (63 patients with insulin dependent diabetes, 13 with non-insulin dependent diabetes). Of the diabetic subjects, 12 had no diabetic retinopathy, 27 had background retinopathy, 13 had pre-proliferative retinopathy, 12 had proliferative retinopathy, and 12 had had pan-retinal photocoagulation for proliferative retinopathy. MAIN OUTCOME MEASURES--Retinal blood flow (microliters/min) and conductance (rate of flow per unit of perfusion pressure). RESULTS--In comparison with non-diabetic controls (9.52 microliters/min) and diabetic patients with no diabetic retinopathy (9.12 microliters/min) retinal blood flow was significantly increased in all grades of untreated diabetic retinopathy (background 12.13 microliters/min, pre-proliferative 15.27 microliters/min, proliferative 13.88 microliters/min). There was a significant decrease in flow after pan-retinal photocoagulation in comparison with all the other groups studied (4.48 microliters/min). Conductance of the retinal circulation was higher in the untreated diabetic retinopathy groups. These results were independent of age, sex, type of diabetes, duration of diabetes, glycated haemoglobin concentration, blood glucose concentration, blood pressure, and intraocular pressure. CONCLUSIONS--Retinal blood flow is significantly increased in diabetic retinopathy in comparison with non-diabetic controls and diabetic subjects with no retinopathy. This has implications for controlling hypertension and hyperglycaemia as a strategy in reducing morbidity from diabetic retinopathy.     

Changes in Inner and Outer Retinal Layer Thicknesses after Vitrectomy for Idiopathic Macular Hole: Implications for Visual Prognosis

Purpose

To investigate sequential post-operative thickness changes in inner and outer retinal layers in eyes with an idiopathic macular hole (MH).

Methods

Retrospective case series. Twenty-four eyes of 23 patients who had received pars plana vitrectomy (PPV) for the closure of MH were included in the study. Spectral domain optical coherence tomography C-scan was used to automatically measure the mean thickness of the inner and outer retinal layers pre-operatively and up to 6 months following surgery. The photoreceptor outer segment (PROS) length was measured manually and was used to assess its relationship with best-corrected visual acuity (BCVA).

Results

Compared with the pre-operative thickness, the inner layers significantly thinned during follow-up (P = 0.02), particularly in the parafoveal (P = 0.01), but not perifoveal, area. The post-operative inner layer thinning ranged from the ganglion cell layer to the inner plexiform layer (P = 0.002), whereas the nerve fiber layer was unaltered. Outer layer thickness was significantly greater post-operatively (P = 0.002), and especially the PROS lengthened not only in the fovea but also in the parafovea (P < 0.001). Six months after surgery, BCVA was significantly correlated exclusively with the elongated foveal PROS (R = 0.42, P = 0.03), but not with any of the other thickness parameters examined.

Conclusions

Following PPV for MH, retinal inner layers other than the nerve fiber layer thinned, suggestive of subclinical thickening in the inner layers where no cyst was evident pre-operatively. In contrast, retinal outer layer thickness significantly increased, potentially as a result of PROS elongation linking tightly with favorable visual prognosis in MH eyes.     

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.     

Visual advantage in deaf adults linked to retinal changes

The altered sensory experience of profound early onset deafness provokes sometimes large scale neural reorganisations. In particular, auditory-visual cross-modal plasticity occurs, wherein redundant auditory cortex becomes recruited to vision. However, the effect of human deafness on neural structures involved in visual processing prior to the visual cortex has never been investigated, either in humans or animals. We investigated neural changes at the retina and optic nerve head in profoundly deaf (N = 14) and hearing (N = 15) adults using Optical Coherence Tomography (OCT), an in-vivo light interference method of quantifying retinal micro-structure. We compared retinal changes with behavioural results from the same deaf and hearing adults, measuring sensitivity in the peripheral visual field using Goldmann perimetry. Deaf adults had significantly larger neural rim areas, within the optic nerve head in comparison to hearing controls suggesting greater retinal ganglion cell number. Deaf adults also demonstrated significantly larger visual field areas (indicating greater peripheral sensitivity) than controls. Furthermore, neural rim area was significantly correlated with visual field area in both deaf and hearing adults. Deaf adults also showed a significantly different pattern of retinal nerve fibre layer (RNFL) distribution compared to controls. Significant correlations between the depth of the RNFL at the inferior-nasal peripapillary retina and the corresponding far temporal and superior temporal visual field areas (sensitivity) were found. Our results show that cross-modal plasticity after early onset deafness may not be limited to the sensory cortices, noting specific retinal adaptations in early onset deaf adults which are significantly correlated with peripheral vision sensitivity.     

Association of contrast sensitivity with LogMAR visual acuity and glycosylated hemoglobin in non-insulin dependent diabetes mellitus

A tertiary care center-based prospective case–control study was undertaken to evaluate the association of contrast sensitivity with LogMAR visual acuity and glycosylated hemoglobin (HbA1c) in 205 cases of non-insulin dependent diabetes mellitus and 115 controls. LogMAR visual acuity and contrast sensitivity were scored using ETDRS and Pelli-Robson charts, respectively. Bivariate correlation between contrast sensitivity and LogMAR visual acuity showed significant inverse correlation in cases without retinopathy (r = −0.466) and with non-proliferative retinopathy (r = −0.307). In a multivariate model, on applying linear regression analysis, LogMAR visual acuity (p < 0.001) and HbA1c (p = 0.002) had significant association with contrast sensitivity. Significant difference in contrast sensitivity was not observed between cases without diabetic retinopathy and with non-proliferative diabetic retinopathy, implying no association with retinal microvascular changes. Contrast sensitivity dysfunction observed in diabetes mellitus results from changes in retinal function secondary to alteration in carbohydrate metabolism depicted in glycosylated hemoglobin.     

Morin attenuates STZ-induced diabetic retinopathy in experimental animals

Diabetic retinopathy (DR) occurs in untreated diabetic patients due to the strong influence of oxidative stress. Bioflavonoids are well known for their antioxidant property. Morin, a bioflavonoid, has been demonstrated for its antioxidant as well as antidiabetic activity. Thus, this research work intended to determine the ameliorative impact of morin in DR rats using STZ-induced type 1 diabetic model. To induce type 1 diabetic in rats STZ (60 mg/kg) was administered intraperitoneally. Grouping of animals was done as described below (n = 6), where, group I – normal control, group II – diabetic control, group III – morin (25 mg/kg), group IV – morin (50 mg/kg), and group V – metformin (350 mg/kg) were used. All the animals underwent treatment for 60 days as given above. It was observed that supplementation of morin (25 and 50 mg/kg) showed a noteworthy decline in elevated serum glucose level. Moreover, decrease in the level of LPO and improved activity of endogenous antioxidants (GPx, CAT, and SOD) was observed in morin treated groups. It also notably drops the concentration of TNF-α, IL-1β, and VEGF in the tissue homogenate of the retina. Furthermore, it increased the retinal thickness and cell count in the ganglion cell layer of the retina in diabetic animals. Hence, we can conclude that morin encumbers the progression of DR in diabetic animals, which may be via antioxidant property and suppression of TNF-α, IL-1β, and VEGF.     

Adeno-Associated Virus Mediated Delivery of a Non-Membrane Targeted Human Soluble CD59 Attenuates Some Aspects of Diabetic Retinopathy in Mice

Diabetic retinopathy is the leading cause of visual dysfunction in working adults and is attributed to retinal vascular and neural cell damage. Recent studies have described elevated levels of membrane attack complex (MAC) and reduced levels of membrane associated complement regulators including CD55 and CD59 in the retina of diabetic retinopathy patients as well as in animal models of this disease. We have previously described the development of a soluble membrane-independent form of CD59 (sCD59) that when delivered via a gene therapy approach using an adeno-associated virus vector (AAV2/8-sCD59) to the eyes of mice, can block MAC deposition and choroidal neovascularization. Here, we examine AAV2/8-sCD59 mediated attenuation of MAC deposition and ensuing complement mediated damage to the retina of mice following streptozotocin (STZ) induced diabetes. We observed a 60% reduction in leakage of retinal blood vessels in diabetic eyes pre-injected with AAV2/8-sCD59 relative to negative control virus injected diabetic eyes. AAV2/8-sCD59 injected eyes also exhibited protection from non-perfusion of retinal blood vessels. In addition, a 200% reduction in retinal ganglion cell apoptosis and a 40% reduction in MAC deposition were documented in diabetic eyes pre-injected with AAV2/8-sCD59 relative to diabetic eyes pre-injected with the control virus. This is the first study characterizing a viral gene therapy intervention that targets MAC in a model of diabetic retinopathy. Use of AAV2/8-sCD59 warrants further exploration as a potential therapy for advanced stages of diabetic retinopathy.     

Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes.

BACKGROUND: Chronic diabetes causes structural changes in the retinal capillaries of nearly all patients with a disease duration of more than 15 years. Acellular occluded vessels cause hypoxia, which stimulates sight-threatening abnormal angiogenesis in 50% of all type I diabetic patients. The mechanism by which diabetes produces acellular retinal capillaries is unknown. MATERIALS AND METHODS: In this study, evidence of programmed cell death (PCD) was sought in the retinas of early diabetic rats, and the effect of nerve growth factor (NGF) on PCD and capillary morphology was evaluated. RESULTS: Diabetes induced PCD primarily in retinal ganglion cells (RGC) and Muller cells. This was associated with a transdifferentiation of Muller cells into an injury-associated glial fibrillary acidic protein (GFAP)-expressing phenotype, and an up-regulation of the low-affinity NGF receptor p75NGFR on both RGC and Muller cells. NGF treatment of diabetic rats prevented both early PCD in RGC and Muller cells, and the development of pericyte loss and acellular occluded capillaries. CONCLUSIONS: These data provide new insight into the mechanism of diabetic retinal vascular damage, and suggest that NGF or other neurotrophic factors may have potential as therapeutic agents for the prevention of human diabetic retinopathy.     

Evaluation of Glaucomatous Damage via Functional Magnetic Resonance Imaging,and Correlations Thereof with Anatomical and Psychophysical Ocular Findings

PurposeTo evaluate the functional magnetic resonance imaging (fMRI) response to binocular visual stimulation and the association thereof with structural ocular findings and psychophysical test results in patients with glaucoma, and controls.MethodsCross-sectional study. Participants underwent a complete ophthalmic examination, including Humphrey 24-2 visual field (VF) testing and optical coherence tomography. Binocular VF in each quadrant was determined using an integrated method. Patients with glaucoma were assigned to three subgroups: initial, asymmetrical and severe glaucoma. Regions of interest (ROIs) were determined anatomically. fMRI (3 T) was performed using a bilaterally presented polar angle stimulus, and the accompanying changes in blood oxygen level-dependent (BOLD) signals were obtained from the occipital poles and calcarine ROIs. We used generalized estimation equation models to compare anatomical and functional data between the groups.ResultsA total of 25 subjects were enrolled, of whom 17 had glaucoma and 8 were controls. Significant associations between quadrant binocular VF sensitivities and fMRI responses were found in the occipital pole ROIs (p = 0.033) and the calcarine ROIs (p = 0.045). In glaucoma severity subgroup analysis, retinal nerve fiber layer (RNFL) thickness was associated with the BOLD response of the calcarine and occipital pole ROIs (p = 0.002 and 0.026, respectively). The initial and asymmetrical glaucoma subgroups had similar binocular VF sensitivities and RNFL thicknesses, but distinct BOLD responses.ConclusionsThe response of the visual cortex to binocular stimulation was associated with binocular VF sensitivity. RNFL thickness was associated with the BOLD response of the calcarine and occipital pole ROIs.     

Effects of prenatal cocaine exposure in the retinal ganglion cell layer of the rat

To study the effects of prenatal cocaine-exposure on the developing retinal ganglion cell layer of the rat, female Wistar rats were administered subcutaneously (sc) cocaine hydrochloride (60 mg/kg body wt/d) or saline, or were not manipulated from gestational d 8–22. Male offspring were sacrificed at postnatal day 14 and 30. Radial semithin sections of epon-embedded flat mounts of the retinal quadrants were used to evaluate the following parameters along the centroperipheral axis:

1. Thickness of ganglion cell plus nerve fiber layer;
2. Nuclear size of ganglion cell layer neurons; and
3. Linear density (number per unit length) of ganglion cell layer neurons.

To study the effects of cocaine and age on the retinal areas (temporal/nasal, dorsal/ventral), a repeated measures analysis of variance was used for each of the parameters mentioned above. All parameters were affected by prenatal exposure to cocaine. The thickness of the ganglion cell plus nerve fiber layer was reduced in cocaine-exposed rats in comparison with the saline group. Nuclear diameters were smaller in the cocaine than in the saline and control groups. The linear density was higher in the cocaine-exposed group than in the control and saline groups. The linear decrease in the linear density from postnatal day 14–30 was higher in the cocaine-exposed rats than in the saline group; the decrease in the linear density along the centroperipheral axis found in both the control and saline groups was not significant in the cocaine-treated group. These morphometric findings strongly support the view that prenatal cocaine-exposure induces marked changes in the organization of the developing retina.     

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.     

Visual Function Assessment in Simulated Real-Life Situations in HIV-Infected Subjects

Visual function abnormalities are common in people living with HIV disease (PLWH) without retinitis, even after improvement in immune status. Abnormalities such as reduced contrast sensitivity, altered color vision, peripheral visual field loss, and electrophysiological changes are related to a combination of retinal dysfunctions, involving inner and outer retinal structures. The standard protocol for testing vision performance in clinical practice is the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. However, this method poorly correlates with activities of daily living that require patients to assess visual stimuli in multiple light/contrast conditions, and with limited time. We utilized a novel interactive computer program (Central Vision Analyzer) to analyze vision performance in PLWH under a variety of light/contrast conditions that simulate stressful and real-world environments. The program tests vision in a time-dependent way that we believe better correlates with daily living activities than the non-timed ETDRS chart. We also aimed to correlate visual scores with retinal neuro-fiber layer thickness on optical coherence tomography. Here we show that visual acuity is more affected in PLWH in comparison to HIV-seronegative controls in varying contrast and luminance, especially if the nadir CD4+ T-cell count was lower than 100 cells/mm³. Visual impairment reflects the loss of retinal nerve fiber layer thickness especially of the temporal-inferior sector. In PLWH the ETDRS chart test led to better visual acuity compared to the Central Vision Analyzer equivalent test, likely because patients had indefinite time to guess the letters. This study confirms and strengthens the finding that visual function is affected in PLWH even in absence of retinitis, since we found that the HIV serostatus is the best predictor of visual loss. The Central Vision Analyzer may be useful in the diagnosis of subclinical HIV-associated visual loss in multiple light/contrast conditions, and may offer better understanding of this entity called “neuroretinal disorder”.     

Caffeic Acid Alkyl Amide Derivatives Ameliorate Oxidative Stress and Modulate ERK1/2 and AKT Signaling Pathways in a Rat Model of Diabetic Retinopathy

The purpose of this study was to examine the neuroprotective effects of caffeic acid hexyl ( CAF6 ) and dodecyl ( CAF12 ) amide derivatives on the early stage of retinopathy in streptozotocin‐induced diabetic rats. Animals were divided in five groups (n=8/group); one group consisted of non‐diabetic rats as control, while the other four were diabetic animals either non‐treated or treated with CAF6 , CAF12 or resveratrol intravitreally for four weeks. Retinal superoxide dismutase (SOD) activity and 8‐iso‐prostaglandin F_2α (iPF_2α) levels were evaluated by an ELISA assay. Phosphorylation of ERK1/2 and AKT was determined by immunoblotting in retinal homogenates. Retinal morphology was also examined using light microscopy. Treatment with CAF6 and CAF12 increased retinal SOD activity, while it decreased iPF_2α levels in diabetic rats. Phosphorylation of ERK1/2 was increased, while AKT phosphorylation was decreased in diabetic rats compared to normal control and these alterations were significantly reversed in diabetic rats treated with CAF6 and CAF12 . Furthermore, thickness of the whole retinal layer, outer nuclear layer, and ganglion cell count were decreased in diabetic rats compared to control and CAF6 and CAF12 treatments prevented these changes. CAF6 and CAF12 seem to be effective agents for treatment of diabetic retinopathy via attenuation of retinal oxidative stress and improvement of neuronal survival signaling.