Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures.
ABSTRACT Pre-clinical trials of treatment in retinal degenerations have shown progress toward preventing loss or restoring function of rod photoreceptors. In anticipation of human clinical trials, we assessed two psychophysical methods of quantifying rod photoreceptor-mediated function as potential outcome measures. Modified automated perimeters were used to deliver focal or full-field light stimuli and dark-adapted thresholds were measured. Patients with retinal degeneration were studied in two experimental protocols. Experiment 1 (n = 35 patients) studied dark-adapted focal chromatic stimuli in central retinal locations along the horizontal meridian. Experiment 2 (n = 146 patients) studied dark-adapted responses to a full-field stimulus test (FST) using white and chromatic stimuli. Patients in both experimental groups had testing on two different visits to determine inter-visit variability. In Experiment 1, two subgroups of patients were identified: a group with a majority of test loci detected by rod photoreceptors and a group with only cone-mediated detection. Inter-visit variability (95% confidence interval) was +/-3.1 dB for normals, +/-3.0 dB for patients with rod-mediated function and +/-2.8 dB for patients with only cone-mediated function. In Experiment 2, the dynamic range of the FST using white stimuli was sufficient to quantify sensitivity in all patients studied, including those with severe retinal degenerations. Chromatic stimuli in the FST were detectable by 85% of patients and rod- or cone-mediation could be determined. Regional retinal sources of FST were explored by comparing FST and dark-adapted perimetry in the same patients; there was a strong correlation between FST level and the loci with highest sensitivity by perimetry. Inter-visit variability (95% confidence interval) in the patients was +/-3.9 dB compared to +/-3.5 dB in normals. Dark-adapted focal threshold measurements with an abbreviated protocol in retinal degeneration patients with stable fixation may be useful as an outcome measure for therapies that can affect rod vision. FST measurements were feasible and reproducible in a large spectrum of retinal degenerative diseases and will be most applicable as a psychophysical outcome measure for treatment trials of very severe disorders in which fixation is lost and there is need for a large dynamic range of stimulus intensity.
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ABSTRACT: The processing of biosignals is increasingly being utilized in ambulatory situations in order to extract significant signals' features that can help in clinical diagnosis. However, this task is hampered by the fact that biomedical signals exhibit a complex behavior characterized by strong nonlinear and non-stationary properties that cannot always be perceived by simple visual examination. New processing methods need be considered. In this context, we propose a signal processing method, based on empirical mode decomposition and artificial neural networks, to analyze electroretinograms, i.e., the retinal response to a light flash, with the aim to detect and classify retinal diseases. The present application focuses on two retinal pathologies: achromatopsia, which is a cone disease, and congenital stationary night blindness, which affects the photoreceptoral signal transmission. The results indicate that, under suitable conditions, the method proposed here has the potential to provide a powerful tool for routine clinical examinations, since it is able to recognize with high level of confidence the eventual presence of one of the two pathologies.Medical & Biological Engineering & Computing 06/2014; DOI:10.1007/s11517-014-1164-8 · 1.50 Impact Factor
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ABSTRACT: Vertebrate species possess two retinal guanylate cyclases (retGC1 and retGC2) and at least two guanylate cyclase activating proteins (GCAPs), GCAP1 and GCAP2. GCAPs function as Ca(2+) sensors that regulate the activity of guanylate cyclases. Together, these proteins regulate cGMP and Ca(2+) levels within the outer segments of rod and cone photoreceptors. Mutations in GUCY2D, the gene that encodes retGC1, are a leading cause of the most severe form of early onset retinal dystrophy, Leber congenital amaurosis (LCA1). These mutations, which reduce or abolish the ability of retGC1 to replenish cGMP in photoreceptors, are thought to lead to the biochemical equivalent of chronic light exposure in these cells. In spite of this, the majority of LCA1 patients retain normal photoreceptor laminar architecture aside from foveal cone outer segment abnormalities, suggesting they may be good candidates for gene replacement therapy. Work began in the 1980s to characterize multiple animal models of retGC1 deficiency. 34 years later, all models have been used in proof of concept gene replacement studies toward the goal of developing a therapy to treat GUCY2D-LCA1. Here we use the results of these studies as well as those of recent clinical studies to address specific questions relating to clinical application of a gene therapy for treatment of LCA1.Frontiers in Molecular Neuroscience 05/2014; 7:43. DOI:10.3389/fnmol.2014.00043
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ABSTRACT: PURPOSE. To investigate visual function and outer and inner retinal structure in the rare form of retinal degeneration (RD) caused byTULP1 (tubby-like protein 1) mutations. METHODS. RD patients with TULP1 mutations (n=5; age range, 5-36 years) were studied by kinetic and chromatic static perimetry, en face autofluoresence imaging and spectral-domain optical coherence tomography (OCT) scans. Outer and inner retinal laminar thickness were measured and mapped across the central retina. Comparisons were made with results from patients with RD associated with four ciliopathy genotypes (MAK, RPGR, BBS1 and USH2A). RESULTS. The TULP1-RD patients were severely affected already in the first decade of life and there was rapidly progressive visual loss. No evidence of rod function was present at any age. Small central islands showed melanized retinal pigment epithelium by autofluorescence imaging and well-preserved photoreceptor laminar thickness by OCT imaging. There was extracentral loss of laminar architecture and increased inner retinal thickening. Structure-function relationships in residual foveal cone islands were made in TULP1-RD patients and in other retinopathies considered ciliopathies. TULP1-RD patients, unlike the others, had greater dysfunction for the degree of foveal structural preservation. CONCLUSIONS. TULP1-RD leads to a small central island of residual foveal cones at early ages. These cones are less sensitive than expected from the residual structure. The human phenotype is consistent with experimental evidence in the Tulp1 knockout mouse model that visual dysfunction could be complicated by abnormal processes proximal to cone outer segments.Investigative Ophthalmology & Visual Science 07/2014; 55(8). DOI:10.1167/iovs.14-14570 · 3.66 Impact Factor