Investigation of adaptive optics imaging biomarkers for detecting pathological changes of the cone mosaic in patients with type 1 diabetes mellitus

Purpose To investigate a set of adaptive optics (AO) imaging biomarkers for the assessment of changes of the cone mosaic spatial arrangement in patients with type 1 diabetes mellitus (DM1). Methods 16 patients with 20/20 visual acuity and a diagnosis of DM1 in the past 8 years to 37 years and 20 age-matched healthy volunteers were recruited in this study. Cone density, cone spacing and Voronoi diagrams were calculated on 160x160 μm images of the cone mosaic acquired with an AO flood illumination retinal camera at 1.5 degrees eccentricity from the fovea along all retinal meridians. From the cone spacing measures and Voronoi diagrams, the linear dispersion index (LDi) and the heterogeneity packing index (HPi) were computed respectively. Logistic regression analysis was conducted to discriminate DM1 patients without diabetic retinopathy from controls using the cone metrics as predictors. Results Of the 16 DM1 patients, eight had no signs of diabetic retinopathy (noDR) and eight had mild nonproliferative diabetic retinopathy (NPDR) on fundoscopy. On average, cone density, LDi and HPi values were significantly different (P<0.05) between noDR or NPDR eyes and controls, with these differences increasing with duration of diabetes. However, each cone metric alone was not sufficiently sensitive to discriminate entirely between membership of noDR cases and controls. The complementary use of all the three cone metrics in the logistic regression model gained 100% accuracy to identify noDR cases with respect to controls. PLOS ONE | DOI:10.1371/journal.pone.0151380 March 10, 2016 1 / 14 OPEN ACCESS Citation: Lombardo M, Parravano M, Serrao S, Ziccardi L, Giannini D, Lombardo G (2016) Investigation of Adaptive Optics Imaging Biomarkers for Detecting Pathological Changes of the Cone Mosaic in Patients with Type 1 Diabetes Mellitus. PLoS ONE 11(3): e0151380. doi:10.1371/journal. pone.0151380 Editor: Knut Stieger, Justus-Liebig-University Giessen, GERMANY Received: December 17, 2015 Accepted: February 27, 2016 Published: March 10, 2016 Copyright: © 2016 Lombardo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Research for this work was supported by the Italian Ministry of Health (5x1000 funding), by the National Framework Program for Research and Innovation PON (grant n. 01_00110) and by Fondazione Roma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Vision Engineering Italy srl funder provided support in the form of salaries for author GL, but did not have any Conclusion The present set of AO imaging biomarkers identified reliably abnormalities in the spatial arrangement of the parafoveal cones in DM1 patients, even when no signs of diabetic retinopathy were seen on fundoscopy

Optical coherence tomography in Alzheimer's disease. A meta-analysis

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. METHODS AND FINDINGS: Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. RESULTS: 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). CONCLUSION: Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber's Hereditary Optic Neuropathy during One Year of Follow-up.

Purpose: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase. Design: Retrospective case series. Participants: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls. Methods: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60ʹ and 15ʹ checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test–retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA. Main Outcome Measures: Changes of individual and mean absolute values of 60ʹ and 15ʹ PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group. Results: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P 0.01) different from baseline values. Conclusions: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON

Bilateral Symmetry of Visual Function Loss in Cone-Rod Dystrophies.

PURPOSE: To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. METHODS: This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms. Interocular agreement in each of these clinical indexes was assessed by t- and Wilcoxon tests for paired samples, structural (Deming) regression analysis, and intraclass correlation. Baseline and follow-up measures were analyzed. A separate analysis was performed on the subset of 61 CRD patients carrying likely disease-causing mutations in the ABCA4 gene. RESULTS: Statistical tests show a very high degree of bilateral symmetry in the extent and progression of visual impairment in the fellow eyes of CRD patients. CONCLUSIONS: These data contribute to a better understanding of CRDs and support the feasibility of clinical trial designs involving unilateral eye treatment with the use of fellow eye as internal control

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

Cytidine 5'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials)

Genotype-phenotype characterization of novel variants in six Italian patients with familial exudative vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family

Retinal and Visual Pathways Involvement in Carriers of Friedreich&rsquo;s Ataxia

Friedreich&rsquo;s ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder due to the homozygous pathological expansion of guanine-adenine-adenine (GAA) triplet repeats in the first intron of the FXN gene, which encodes for the mitochondrial protein frataxin. In the visual system, the typical manifestations are ocular motility abnormality, optic neuropathy, and retinopathy. Despite the evidence of ophthalmological impairment in FRDA patients, there is a lack of information about the morpho-functional condition of the retina and of the optic pathways in healthy heterozygous carriers of Friedreich&rsquo;s ataxia (C-FRDA). Ten C-FRDA subjects (providing 20 eyes) and thirty-five Controls (providing 70 eyes) underwent a complete neurological and ophthalmological examination comprehensive of functional (full-field Electroretinogram (ffERG), multifocal Electroretinogram (mfERG), Visual Evoked Potential (VEP), and Pattern Reversal Electroretinogram (PERG)) and morphological assessments (Optical Coherence Tomography, OCT) of the retina, macula, retinal ganglion cells, and visual pathways. The groups&rsquo; data were compared using a two-sample t-test. Pearson&rsquo;s test was used to investigate the morpho-functional correlations. Statistically significant differences (p &lt; 0.01) between C-FRDA and Control eyes for the values of the following parameters were found: ffERG b-wave amplitude, mfERG Response Amplitude Densities, PERG P50 implicit time and P50-N95 amplitude, VEP P100 implicit time, Retinal Nerve Fiber Layer (RNFL) Overall, and Nasal thickness. The values of the OCT macular volume were not statistically different (p &gt; 0.01) between the two Groups. Therefore, our data suggest that, in C-FRDA, a dysfunction of retinal elements without morphological macular impairment may occur. In addition, a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be also detected

Functional Assessment of Outer and Middle Macular Layers in Multiple Sclerosis

The involvement of macular preganglionic elements&rsquo; function, during the neurodegenerative process of multiple sclerosis (MS), is controversial. In this case-control observational and retrospective study, we assessed multifocal electroretinogram (mfERG) responses from 41 healthy Controls, 41 relapsing-remitting MS patients without optic neuritis (ON) (MS-noON Group) and 47 MS patients with ON: 27 with full recovery of high-contrast best corrected visual acuity (BCVA) (MS-ON-G Group) and 20 with poor recovery (between 0.2 and 1 LogMAR) of BCVA, (MS-ON-P Group). In the latter Group, Sd-OCT macular volumes and thicknesses of whole and inner and outer retina were measured. MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs), were measured from concentric rings (R) with increasing foveal eccentricity: 0&ndash;5&deg; (R1), 5&ndash;10&deg; (R2), 10&ndash;15&deg; (R3), 15&ndash;20&deg; (R4), 20&ndash;25&deg; (R5), and from retinal sectors (superior, nasal, inferior and temporal) between 0&ndash;15&deg; and 0&ndash;25&deg;. In the MS-ON-P Group, mean mfERG RADs detected from R1 (0&ndash;5&deg;) and from the central nasal sector (0&ndash;15&deg;) were significantly reduced (p &lt; 0.01) with respect to those of the Control, MS-noON and MS-ON-G Groups. No other significant differences between Groups for any mfERG parameters were found. All Sd-OCT measurements, apart from the inner retina macular volume in the central 1 mm, were significantly reduced in MS-ON-P patients compared to Controls. The functional impairment in the MS-ON-P Group was associated but not correlated with structural changes of the outer and inner retinal layers in corresponding retinal Areas and Sectors. Our results suggest that in MS, exclusively after ON with poor recovery of BCVA, the neurodegenerative process can induce dysfunctional mechanisms involving photoreceptors and bipolar cells of the fovea and of the more central nasal macular area