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Increasing evidence suggests that the conditions of retinal microvessels are indicators to a variety of cerebrovascular, neurodegenerative, psychiatric, and developmental diseases. Thus noninvasive visualization of the human retinal microcirculation offers an exceptional opportunity for the investigation of not only the retinal but also cerebral microvasculature. In this review, we show how the conditions of the retinal microvessels could be used to assess the conditions of brain microvessels because the microvascular network of the retina and brain share, in many aspects, standard features in development, morphology, function, and pathophysiology. Recent techniques and imaging modalities, such as optical coherence tomography (OCT), allow more precise visualization of various layers of the retina and its microcirculation, providing a "microscope" to brain microvessels. We also review the potential role of retinal microvessels in the risk identification of cerebrovascular and neurodegenerative diseases. The association between vision problems and cerebrovascular and neurodegenerative diseases, as well as the possible role of retinal microvascular imaging biomarkers in cerebrovascular and neurodegenerative screening, their potentials, and limitations, are also discussed.
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Trastornos Cerebrovasculares/diagnóstico por imagen , Microvasos/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Células Ganglionares de la Retina/patología , Vasos Retinianos/diagnóstico por imagen , Angiografía , Encéfalo , Circulación Cerebrovascular , Trastornos Cerebrovasculares/patología , Fondo de Ojo , Humanos , Microvasos/patología , Enfermedades Neurodegenerativas/patología , Neuronas/patología , Vasos Retinianos/patología , Tomografía de Coherencia ÓpticaRESUMEN
The ex vivo human skin wound model is a widely accepted model to study wound epithelialization. Due to a lack of animal models that fully replicate human conditions, the ex vivo model is a valuable tool to study mechanisms of wound reepithelialization, as well as for preclinical testing of novel therapeutics. The current standard for assessment of wound healing in this model is histomorphometric analysis, which is labor intensive, time consuming, and requires multiple biological and technical replicates in addition to assessment of different time points. Optical coherence tomography (OCT) is an emerging noninvasive imaging technology originally developed for noninvasive retinal scans that avoids the deleterious effects of tissue processing. This study investigated OCT as a novel method for assessing reepithelialization in the human ex vivo wound model. Excisional ex vivo wounds were created, maintained at air-liquid interface, and healing progression was assessed at days 4 and 7 with OCT and histology. OCT provided adequate resolution to identify the epidermis, the papillary and reticular dermis, and importantly, migrating epithelium in the wound bed. We have deployed OCT as a noninvasive tool to produce, longitudinal "optical biopsies" of ex vivo human wound healing process, and we established an optimal quantification method of re-epithelialization based on en face OCT images of the total wound area. Pairwise statistical analysis of OCT and histology based quantifications for the rate of epithelialization have shown the feasibility and superiority of OCT technology for noninvasive monitoring of human wound epithelialization. Furthermore, we have utilized OCT to evaluate therapeutic potential of allogeneic adipose stem cells revealing their ability to promote reepithelialization in human ex vivo wounds. OCT technology is promising for its applications in wound healing and evaluation of novel therapeutics in both the laboratory and the clinical settings.
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Repitelización , Piel/diagnóstico por imagen , Heridas y Lesiones/diagnóstico por imagen , Adulto , Dermis/diagnóstico por imagen , Dermis/patología , Epidermis/diagnóstico por imagen , Epidermis/patología , Humanos , Persona de Mediana Edad , Piel/lesiones , Piel/patología , Trasplante de Células Madre , Grasa Subcutánea/citología , Tomografía de Coherencia Óptica , Heridas y Lesiones/patologíaRESUMEN
BACKGROUND: To investigate the influence of scan distance on retinal boundary detection errors (RBDEs) and retinal thickness measurements by spectral domain optical coherence tomography (SD-OCT). METHODS: 10 eyes of healthy subjects, 10 eyes with diabetic macular edema (DME) and 10 eyes with neovascular age-related macular degeneration (AMD) were examined with RTVue SD-OCT. The MM5 protocol was used in two consecutive sessions to scan the macula. For the first session, the device was set 3.5 cm from the eye in order to obtain detectable signal with low fundus image quality (suboptimal setting) while in the second session a distance of 2.5 cm was set with a good quality fundus image. The signal strength (SSI) value was recorded. The score for retinal boundary detection errors (RBDE) was calculated for ten scans of each examination. RBDE scores were recorded for the whole scan and also for the peripheral 1.0 mm region. RBDE scores, regional retinal thickness values and SSI values between the two sessions were compared. The correlation between SSI and the number of RBDEs was also examined. RESULTS: The SSI was significantly lower with suboptimal settings compared to optimal settings (63.9±12.0 vs. 68.3±12.2, respectively, p = 0.001) and the number of RBDEs was significantly higher with suboptimal settings in the "all-eyes" group along with the group of healthy subjects and eyes with DME (9.1±6.5 vs. 6.8±6.3, p = 0.007; 4.4±2.6 vs. 2.5±1.6, p = 0.035 and 9.7±3.3 vs. 5.1±3.7, p = 0.008, respectively). For these groups, significant negative correlation was found between the SSI and the number of RBDEs. In the AMD group, the number of RBDEs was markedly higher compared to the other groups and there was no difference in RBDEs between optimal and suboptimal settings with the errors being independent of the SSI. There were significantly less peripheral RBDEs with optimal settings in the "all-eyes" group and the DME subgroup (2.7±2.6 vs. 4.2±2.8, p = 0.001 and 1.4±1.7 vs. 4.1±2.2, p = 0.007, respectively). Retinal thickness in the two settings was significantly different only in the outer-superior region in DME. CONCLUSIONS: Optimal distance settings improve SD-OCT SSI with a decrease in RBDEs while retinal thickness measurements are independent of scanning distance.
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Retinopatía Diabética/diagnóstico , Errores Diagnósticos , Edema Macular/diagnóstico , Retina/patología , Tomografía de Coherencia Óptica/métodos , Degeneración Macular Húmeda/diagnóstico , Estudios Transversales , Voluntarios Sanos , Humanos , Tamaño de los Órganos , Estudios ProspectivosRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0271156.].
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PURPOSE: For the training of machine learning (ML) algorithms, correctly labeled ground truth data are inevitable. In this pilot study, we assessed the performance of graders with different backgrounds in the labeling of retinal fundus image quality. METHODS: Color fundus photographs were labeled using a Python-based tool using four image categories: excellent (E), good (G), adequate (A) and insufficient for grading (I). We enrolled 8 subjects (4 with and 4 without medical background, groups M and NM, respectively) to whom a tutorial was presented on image quality requirements. We randomly selected 200 images from a pool of 18,145 expert-labeled images (50/E, 50/G, 50/A, 50/I). The performance of the grading was timed and the agreement was assessed. An additional grading round was performed with 14 labels for a more objective analysis. RESULTS: The median time (interquartile range) for the labeling task with 4 categories was 987.8 sec (418.6) for all graders and 872.9 sec (621.0) vs. 1019.8 sec (479.5) in the M vs. NM groups, respectively. Cohen's weighted kappa showed moderate agreement (0.564) when using four categories that increased to substantial (0.637) when using only three by merging the E and G groups. By the use of 14 labels, the weighted kappa values were 0.594 and 0.667 when assigning four or three categories, respectively. CONCLUSION: Image grading with a Python-based tool seems to be a simple yet possibly efficient solution for the labeling of fundus images according to image quality that does not necessarily require medical background. Such grading can be subject to variability but could still effectively serve the robust identification of images with insufficient quality. This emphasizes the opportunity for the democratization of ML-applications among persons with both medical and non-medical background. However, simplicity of the grading system is key to successful categorization.
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Técnicas de Diagnóstico Oftalmológico , Fotograbar , Fondo de Ojo , Humanos , Fotograbar/métodos , Proyectos Piloto , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Diabetic Retinopathy (DR) is a severe and widely spread eye disease. Thus, an objective test for the early diagnosis and evaluation of treatment in DR is certainly needed. In this study, the ability of intraretinal layer segmentation to locally detect early retinal changes in diabetic patients is assessed using optical coherence tomography (OCT). MATERIAL/METHODS: Fifty diabetic patients with no or minimal DR underwent ophthalmic examination, OCT and fundus photography. Automated segmentation of intraretinal layers of the OCT images was performed using a custom-built algorithm. Mean thickness of the macula and intraretinal layers of patients with no DR (DM) was calculated in the fovea, pericentral and peripheral regions and compared with those in patients with mild DR (MDR). RESULTS: We found reduced retinal nerve fiber layer (RNFL) thickness in the pericentral and peripheral regions (27 + or - 2 versus 18 + or - 5 microm and 42 + or - 3 versus 33 + or - 9 microm, respectively, p<0.001) and reduced thickness of ganglion cell/inner plexiform layer (GCL+IPL) complex in the pericentral region of the macula (92 + or - 7 microm versus 80 + or - 10 microm, p<0.001) in the MDR group. Accordingly, macular thickness was reduced in the pericentral and peripheral region of the macula in the MDR group. CONCLUSIONS: Our results support the view of neurodegeneration in diabetes in the early stage of retinopathy which seems to involve the ganglion cells and cells of the inner plexiform layers (RNFL+GCL+IPL) mostly. Local retinal thickness measures can be obtained from OCT scans using an intraretinal layer segmentation procedure, and these measures could be helpful in finding a surrogate for following development of retinopathy that could affect vision.
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Diabetes Mellitus/patología , Retina/patología , Tomografía de Coherencia Óptica/métodos , Adulto , Femenino , Humanos , Mácula Lútea/patología , Masculino , Persona de Mediana Edad , Programas InformáticosRESUMEN
Retinal blood flow (RBF) information has the potential to offer insight into ophthalmic health and disease that is complementary to traditional anatomical biomarkers as well as to retinal perfusion information provided by fluorescence or optical coherence tomography angiography (OCT-A). The present study was performed to test the functional attributes and performance of the XyCAM RI, a non-invasive imager that obtains and assesses RBF information. The XyCAM RI was installed and used in two different settings to obtain video recordings of the blood flow in the optic nerve head region in eyes of healthy subjects. The mean blood flow velocity index (BFVi) in the optic disc and in each of multiple arterial and venous segments was obtained and shown to reveal a temporal waveform with a peak and trough that correlates with a cardiac cycle as revealed by a reference pulse oximeter (correlation between respective peak-to-peak distances was 0.977). The intra-session repeatability of the XyCAM RI was high with a coefficient of variation (CV) of 1.84 ± 1.13% across both sites. Artery-vein comparisons were made by estimating, in a pair of adjacent arterial and venous segments, various temporal waveform metrics such as pulsatility index, percent time in systole and diastole, and change in vascular blood volume over a cardiac cycle. All arterial metrics were shown to have significant differences with venous metrics (p < 0.001). The XyCAM RI, therefore, by obtaining repeatable blood flow measurements with high temporal resolution, permits the differential assessment of arterial and venous blood flow patterns in the retina that may facilitate research into disease pathophysiology and biomarker development for diagnostics.
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Disco Óptico/irrigación sanguínea , Vasos Retinianos/diagnóstico por imagen , Grabación en Video/instrumentación , Adulto , Equipos y Suministros , Femenino , Angiografía con Fluoresceína , Voluntarios Sanos , Hemodinámica , Humanos , Masculino , Disco Óptico/diagnóstico por imagen , Flujo Sanguíneo Regional , Tomografía de Coherencia ÓpticaRESUMEN
Evidence is accumulating that cognitive function, and visual impairment may be related. In this pilot study, we investigated whether multifractal dimension and lacunarity analyses performed in sectoral regions of the retina may reveal changes in patients with cognitive impairment (CI) that may be masked in the study considering the whole retinal branching pattern. Prospective age-matched subjects (n = 69) with and with no CI and without the presence of any ophthalmic history were recruited (age > 55+ years). The Montreal Cognitive Assessment (MoCA) was used to measure CI, and full-field electroretinogram (ERG) was performed. Also, visual performance exams were conducted using the Rabin cone contrast test (CCT). Quantification of the retinal structure was performed in retinal fundus images [45 o field of view (FOV), optic disk centered] with excellent quality for all individuals [19 healthy controls (HC) and 20 patients with CI] after evaluating the inclusion and exclusion criteria in all study participants recruited (n = 69). The skeletonized vasculature network that comprised the whole branching pattern observable in the full 45° FOV was obtained for each image and divided into nine equal regions (superotemporal, superior, superonasal, macular, optic disk, nasal, inferotemporal, inferior, and inferonasal). The multifractal behavior was analyzed by calculating the generalized dimension Dq (Do, D1, and D2), the lacunarity parameter (Λ), and singularity spectrum f(α) in the nine sectoral skeletonized images as well as in the skeletons that comprised the whole branching pattern observable in the full 45° FOV. The analyses were performed using the ImageJ program together with the FracLac plug-in. Independent sample t-tests or Mann Whitney U test and Pearson correlation coefficient were used to find associations between all parameters in both groups. The effect size (Cohen's d) of the difference between both groups was also assessed. A p-value < 0.05 was considered statistically significant. Significant correlations between multifractal and Λ parameters with the MoCA and implicit time ERG-parameter were observed in the regional analysis. In contrast, no trend was found when considering the whole retinal branching pattern. Analysis of combined structural-functional parameters in sectoral regions of the retina, instead of individual retinal biomarkers, may provide a useful clinical marker of CI.
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This review will highlight recent insights into measuring retinal structure in Alzheimer's disease (AD). A growing body of evidence indicates that disturbances in retinal blood flow and structure are related to cognitive function, which can severely impair vision. Optical coherence tomography (OCT) is an optical imaging technology that may allow researchers and physicians to gain deeper insights into retinal morphology and clarify the impact of AD on retinal health and function. Direct and noninvasive measurement of retinal morphology using OCT has provided useful diagnostic and therapeutic indications in several central nervous system (CNS) diseases, including AD, multiple sclerosis, and Parkinson disease. Despite several limitations, morphology assessment in the retinal layers is a significant advancement in the understanding of ocular diseases. Nevertheless, additional studies are required to validate the use of OCT in AD and its complications in the eye.
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Previous studies have demonstrated that cognitive impairment (CI) is not limited to the brain but also affects the retina. In this pilot study, we investigated the correlation between the retinal vascular complexity and neurodegenerative changes in patients with CI using a low-cost multimodal approach. Quantification of the retinal structure and function were conducted for every subject (n = 69) using advanced retinal imaging, full-field electroretinogram (ERG) and visual performance exams. The retinal vascular parameters were calculated using the Singapore Institute Vessel Assessment software. The Montreal Cognitive Assessment was used to measure CI. Pearson product moment correlation was performed between variables. Of the 69 participants, 32 had CI (46%). We found significantly altered microvascular network in individuals with CI (larger venular-asymmetry factor: 0.7 ± 0.2) compared with controls (0.6 ± 0.2). The vascular fractal dimension was lower in individuals with CI (capacity, information and correlation dimensions: D0, D1, and D2 (mean ± SD): 1.57 ± 0.06; 1.56 ± 0.06; 1.55 ± 0.06; age 81 ± 6years) vs. controls (1.61 ± 0.03; 1.59 ± 0.03; 1.58 ± 0.03; age: 80 ± 7 years). Also, drusen-like regions in the peripheral retina along with pigment dispersion were noted in subjects with mild CI. Functional loss in color vision as well as smaller ERG amplitudes and larger peak times were observed in the subjects with CI. Pearson product moment correlation showed significant associations between the vascular parameters (artery-vein ratio, total length-diameter ratio, D0, D1, D2 and the implicit time (IT) of the flicker response but these associations were not significant in the partial correlations. This study illustrates that there are multimodal retinal markers that may be sensitive to CI decline, and adds to the evidence that there is a statistical trend pointing to the correlation between retinal neuronal dysfunction and microvasculature changes suggesting that retinal geometric vascular and functional parameters might be associated with physiological changes in the retina due to CI. We suspect our analysis of combined structural-functional parameters, instead of individual biomarkers, may provide a useful clinical marker of CI that could also provide increased sensitivity and specificity for the differential diagnosis of CI. However, because of our study sample was small, the full extent of clinical applicability of our approach is provocative and still to be determined.
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In this study, we examined the relationship between the fractal dimension (FD), the morphology of the foveal avascular zone (FAZ) and the macular circulation in healthy controls and patients with type 2 diabetes mellitus (T2DM) with and with no diabetic retinopathy (DR). Cross-sectional data of 47 subjects were analyzed from a 5-year longitudinal study using a multimodal optical imaging approach. Healthy eyes from nondiabetic volunteers (n = 12) were selected as controls. Eyes from patients with T2DM were selected and divided into two groups: diabetic subjects with mild DR (MDR group, n = 15) and subjects with DM but without DR (DM group, n = 20). Our results demonstrated a higher FD in the healthy group (mean, 1.42 ± 0.03) than in the DM and MDR groups (1.39 ± 0.02 and 1.35 ± 0.03, respectively). Also, a bigger perimeter, area, and roundness of the FAZ were found in MDR eyes. A significant difference in area and perimeter (p ≤ 0.005) was observed for the MDR group supporting the enlargement of the FAZ due to diabetic complications in the eye. A moderate positive correlation (p = 0.014, R2 = 43.8%) between the FD and blood flow rate (BFR) was only found in the healthy control group. The BFR calculations revealed the lowest values in the MDR group (0.98 ± 0.27 µl/s vs. 1.36 ± 0.86 µl/s and 1.36 ± 0.57 µl/sec in the MDR, DM, and healthy groups, respectively, p = 0.2). Our study suggests that the FD of the foveal vessel arborization could provide useful information to identify early morphological changes in the retina of patients with T2DM. Our results also indicate that the enlargement and asymmetry of the FAZ might be related to a lower BFR because of the DR onset and progression. Interestingly, due to the lack of FAZ symmetry observed in the DM and MDR eyes, it appears that the distribution of flow within the retinal vessels loses complexity as the vascular structures distributing the flow are not well described by fractal branching. Further research could determine how our approach may be used to aid the diagnosis of retinal neurodegeneration and vascular impairment at the early stage of DR.
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Diabetic Retinopathy (DR) is an extremely severe and common degenerative disease. The purpose of this study was to quantify the relationship between various parameters including the Foveal Avascular Zone (FAZ) morphology, retinal layer thickness, and retinal hemodynamic properties in healthy controls and patients with diabetes mellitus (DM) with and with no mild DR (MDR) using Spectral-Domain Optical Coherence Tomography (Spectralis SDOCT, Heidelberg Engineering GmbH, Germany) and the Retinal Function Imager (Optical Imaging, Ltd., Rehovot, Israel). Our results showed a higher FAZ area and diameter in MDR patients. Blood flow analysis also showed that there is a significantly smaller venous blood flow velocity in MDR patients. Also, a significant difference in roundness was observed between DM and MDR groups supporting the development of asymmetrical FAZ expansion with worsening DR. Our results suggest a potential anisotropy in the mechanical properties of the diabetic retina with no retinopathy that may trigger the FAZ elongation in a preferred direction resulting in either thinning or thickening of intraretinal layers in the inner and outer segments of the retina as a result of autoregulation. A detailed understanding of these relationships may facilitate earlier detection of DR, allowing for preservation of vision and better clinical outcomes.
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Diabetes Mellitus/fisiopatología , Retinopatía Diabética/fisiopatología , Mácula Lútea/irrigación sanguínea , Flujo Sanguíneo Regional , Vasos Retinianos/patología , Vasos Retinianos/fisiopatología , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Coherencia Óptica/métodosRESUMEN
PURPOSE: To assess the differences in texture descriptors and optical properties of retinal tissue layers in patients with multiple sclerosis (MS) and to evaluate their usefulness in the detection of neurodegenerative changes using optical coherence tomography (OCT) image segmentation. PATIENTS AND METHODS: 38 patients with MS were examined using Stratus OCT. The raw macular OCT data were exported and processed using OCTRIMA software. The enrolled eyes were divided into two groups, based on the presence of optic neuritis (ON) in the history (MSON+ group, n = 36 and MSON- group, n = 31). Data of 29 eyes of 24 healthy subjects (H) were used as controls. A total of seven intraretinal layers were segmented and thickness as well as optical parameters such as contrast, fractal dimension, layer index and total reflectance were measured. Mixed-model ANOVA analysis was used for statistical comparisons. RESULTS: Significant thinning of the retinal nerve fiber layer (RNFL), ganglion cell/inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, RNFL+GCL+IPL) was observed between study groups in all comparisons. Significant difference was found in contrast in the RNFL, GCL+IPL, GCC, inner nuclear layer (INL) and outer plexiform layer when comparing MSON+ to the other groups. Higher fractal dimension values were observed in GCL+IPL and INL layers when comparing H vs. MSON+ groups. A significant difference was found in layer index in the RNFL, GCL+IPL and GCC layers in all comparisons. A significant difference was observed in total reflectance in the RNFL, GCL+IPL and GCC layers between the three examination groups. CONCLUSION: Texture and optical properties of the retinal tissue undergo pronounced changes in MS even without optic neuritis. Our results may help to further improve the diagnostic efficacy of OCT in MS and neurodegeneration.
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Esclerosis Múltiple/patología , Retina/patología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: To evaluate and compare thickness changes in the retinal layers in the macula with optical coherence tomography (OCT) segmentation software after femtosecond laser-assisted phacoemulsification (study group) and conventional phacoemulsification (control group). SETTING: Department of Ophthalmology, Semmelweis University, Budapest, Hungary. DESIGN: Case-control study. METHODS: Total retinal thickness of the macula was evaluated using Stratus OCT 4 to 8 weeks postoperatively. The OCT images were segmented using OCT retinal image analysis software. Regional thickness data in the central area, inner rings, and outer rings were obtained and absolute and relative thicknesses of the individual retinal layers in the 2 study groups compared. Relative thickness was calculated as the ratio of the retinal layer to the total retinal thickness. RESULTS: All surgeries were uneventful. Statistically significant differences were found in absolute outer nuclear layer thickness and relative outer nuclear layer thickness in the inner and outer macular rings between the 2 groups. After adjusting for effective phaco time in multivariate modeling, type of surgery showed a significantly lower relative outer nuclear layer ratio in the inner retinal ring (0.26 with 95% confidence interval [CI], 0.25-0.27 versus 0.28 with 95% CI, 0.27-0.29; P=.03) and in the outer retinal ring (0.27 with 95% CI, 0.25-0.28 versus 0.29 with 95% CI, 0.28-0.31; P=.02) in the study group. CONCLUSION: After cataract surgery, macular edema was detectable mainly in the outer nuclear layer in both groups but was significantly less using the femtosecond laser platform.