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Artificial intelligence has transformed medical diagnostic capabilities, particularly through medical image analysis. AI algorithms perform well in detecting abnormalities with a strong performance, enabling computer-aided diagnosis by analyzing the extensive amounts of patient data. The data serve as a foundation upon which algorithms learn and make predictions. Thus, the importance of data cannot be underestimated, and clinically corresponding datasets are required. Many researchers face a lack of medical data due to limited access, privacy concerns, or the absence of available annotations. One of the most widely used diagnostic tools in ophthalmology is Optical Coherence Tomography (OCT). Addressing the data availability issue is crucial for enhancing AI applications in the field of OCT diagnostics. This review aims to provide a comprehensive analysis of all publicly accessible retinal OCT datasets. Our main objective is to compile a list of OCT datasets and their properties, which can serve as an accessible reference, facilitating data curation for medical image analysis tasks. For this review, we searched through the Zenodo repository, Mendeley Data repository, MEDLINE database, and Google Dataset search engine. We systematically evaluated all the identified datasets and found 23 open-access datasets containing OCT images, which significantly vary in terms of size, scope, and ground-truth labels. Our findings indicate the need for improvement in data-sharing practices and standardized documentation. Enhancing the availability and quality of OCT datasets will support the development of AI algorithms and ultimately improve diagnostic capabilities in ophthalmology. By providing a comprehensive list of accessible OCT datasets, this review aims to facilitate better utilization and development of AI in medical image analysis.
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Background: This pilot study aimed to evaluate the Retinal Function Imager (RFI) for visualizing retinal vasculature and assessment of blood flow characteristics in patients with retinal vasculitis. The RFI is a non-invasive imaging device measuring the blood flow velocity (BFV) in secondary and tertiary retinal vessels using hemoglobin as an intrinsic motion-contrast agent. Methods: To test the feasibility of the RFI for patients with retinal vasculitis, capillary perfusion maps (nCPMs) were generated from 15 eyes of eight patients (five females; mean age: 49 ± 12 years) with a mean uveitis duration of 74 ± 85 months. Five of these patients had birdshot chorioretinopathy, and three had primarily non-occlusive venous retinal vasculitis of unknown origin. To reflect that the BFV may be more reduced in patients with prolonged disease, patients were classified into a short-term (uveitis duration: 8-15 months) and a long-term uveitis group (uveitis duration: 60-264 months). Data were compared with healthy controls (16 eyes of 11 patients; mean age 45 ± 12 years; 8 females). Results: The mean BFV in the controls was 3.79 ± 0.50 mm/s in the retinal arteries and 2.35 ± 0.44 mm/s in the retinal veins, which was significantly higher compared to the retinal vasculitis group. Patients revealed an arterial BFV of 2.75 ± 0.74 mm/s (p < 0.001) and a venous BFV of 1.75 ± 0.51 mm/s (p = 0.016). In the short-term group, a trend towards a decreased venular and arteriolar BFV was seen, while a significant reduction was observed in the long-term group. The patients' microvasculature anatomy revealed by the nCPMs appeared unevenly distributed and a lower number of blood vessels were seen, along with a lower degree of complexity of their branching patterns, when compared with controls. Conclusions: This study demonstrated a reduction in venular and arteriolar BFVs in patients with retinal vasculitis. BFV alterations were already observed in early disease stages and became more pronounced in progressed disease. Additionally, we showed that retinal microvasculature changes may be observed by nCPMs. Retinal imaging with the RFI may serve as a diagnostic and quantifying tool in retinal vasculitis.
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Electroretinography (ERG) provides crucial insights into retinal function and the integrity of the visual pathways. However, ERG assessments classically require a complicated technical background with costly equipment. In addition, the placement of corneal or conjunctival electrodes is not always tolerated by the patients, which restricts the measurement for pediatric evaluations. In this short review, we give an overview of the use of the RETeval portable ERG device (LKC Technologies, Inc., Gaithersburg, MD, USA), a modern portable ERG device that can facilitate screening for diseases involving the retina and the optic nerve. We also review its potential to provide ocular biomarkers in systemic pathologies, such as Alzheimer's disease and central nervous system alterations, within the framework of oculomics.
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Eletrorretinografia , Desenho de Equipamento , Doenças Retinianas , Humanos , Eletrorretinografia/instrumentação , Eletrorretinografia/economia , Doenças Retinianas/diagnóstico , Análise de Falha de Equipamento , Miniaturização , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Programas de Rastreamento/instrumentação , Programas de Rastreamento/economia , Seleção Visual/instrumentação , Seleção Visual/economia , Custos de Cuidados de SaúdeRESUMO
This comprehensive review explores the role of Functional Near-Infrared Spectroscopy (fNIRS) in advancing our understanding of the visual system. Beginning with an introduction to fNIRS, we delve into its historical development, highlighting how this technology has evolved over time. The core of the review critically examines the advantages and disadvantages of fNIRS, offering a balanced view of its capabilities and limitations in research and clinical settings. We extend our discussion to the diverse applications of fNIRS beyond its traditional use, emphasizing its versatility across various fields. In the context of the visual system, this review provides an in-depth analysis of how fNIRS contributes to our understanding of eye function, including eye diseases. We discuss the intricacies of the visual cortex, how it responds to visual stimuli and the implications of these findings in both health and disease. A unique aspect of this review is the exploration of the intersection between fNIRS, virtual reality (VR), augmented reality (AR) and artificial intelligence (AI). We discuss how these cutting-edge technologies are synergizing with fNIRS to open new frontiers in visual system research. The review concludes with a forward-looking perspective, envisioning the future of fNIRS in a rapidly evolving technological landscape and its potential to revolutionize our approach to studying and understanding the visual system.
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[This corrects the article DOI: 10.1371/journal.pone.0271156.].
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BACKGROUND: Visual impairment could worsen sleep/wake disorders and cognitive decline. OBJECTIVE: To examine interrelations among self-reported visual impairment, sleep, and cognitive decline in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Miami-site. METHOD: HCHS/SOL Miami-site participants ages 45-74 years (nâ=â665) at Visit-1, who returned for cognitive test 7-years later (SOL-INCA). Participants completed the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ), validated sleep questionnaires and test for obstructive sleep apnea (OSA) at Visit-1. We obtained verbal episodic learning and memory, verbal fluency, processing speed, and executive functioning at Visit-1 and at SOL-INCA. Processing speed/executive functioning were added to SOL-INCA. We examined global cognition and change using a regression-based reliable change index, adjusting for the time lapse between Visit-1 and SOL-INCA. We used regression models to test whether 1) persons with OSA, self-reported sleep duration, insomnia, and sleepiness have an increased risk for visual impairment, 2a) visual impairment is associated with worse cognitive function and/or decline, and 2b) sleep disorders attenuate these associations. RESULT: Sleepiness (ß=â0.04; pâ<â0.01) and insomnia (ß=â0.04; pâ<â0.001) were cross-sectionally associated with visual impairment, adjusting for sociodemographic characteristics, behavioral factors, acculturation, and health conditions. Visual impairment was associated with lower global cognitive function at Visit-1 (ß=â-0.16; pâ<â0.001) and on average 7-years later (ß=â-0.18; pâ<â0.001). Visual impairment was also associated with a change in verbal fluency (ß=â-0.17; pâ<â0.01). OSA, self-reported sleep duration, insomnia, and sleepiness did not attenuate any of the associations. CONCLUSION: Self-reported visual impairment was independently associated with worse cognitive function and decline.
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Disfunção Cognitiva , Hispânico ou Latino , Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Transtornos da Visão , Idoso , Humanos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etnologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Hispânico ou Latino/psicologia , Autorrelato , Sono , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/etnologia , Apneia Obstrutiva do Sono/psicologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/etnologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Sonolência , Transtornos da Visão/complicações , Transtornos da Visão/diagnóstico , Transtornos da Visão/etnologia , Transtornos da Visão/psicologia , Pessoa de Meia-Idade , Duração do Sono , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/etnologia , Distúrbios da Fala/etiologia , Distúrbios da Fala/psicologiaRESUMO
Regular physical exercise is known to lower the incidence of age-related eye diseases. We aimed to assess the acute chorioretinal alterations in older adults following intense physical strain. Seventeen senior elite athletes were recruited who underwent an aerobic exercise on a cycle ergometer and macular scanning by optical coherence tomography. A significant thinning of the entire retina was observed 1 min after exercise, followed by a thickening at 5 min, after which the thickness returned to baseline. This trend was similar in almost every single retinal layer, although a significant change was observed only in the inner retina. Choroidal thickness changes were neither significant nor did they correlate with the thickness changes of intraretinal layers. The mechanism of how these immediate retinal changes chronically impact age-related sight-threatening pathologies that, in turn, result in a substantially reduced quality of life warrants further investigation on nontrained older adults as well.
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Qualidade de Vida , Retina , Humanos , Idoso , Retina/diagnóstico por imagem , Retina/patologia , Corioide/diagnóstico por imagem , Corioide/patologia , Exercício Físico , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: The study aimed to evaluate the changes in retinal vascular density in exudative age-related macular degeneration (AMD) after long-term anti-VEGF treatment using optical coherence tomography angiography (OCT-A), and to compare these changes with the vascular density in AMD treated for one year and healthy eyes. METHODS: In our cross-sectional study OCT-A was performed on 60 eyes of 60 patients. Group AMD 20 × consisted of patients receiving long-term (minimum 20 injections) aflibercept therapy (n = 17), and Group AMD one year consisted of patients treated for one year with a treat & extend protocol (n = 25). The vascular density values obtained with OCT-A were compared with an age-matched control group of 18 healthy eyes. We examined the central retinal thickness (CRT), the vascular density of the fovea and parafovea in the superficial and deep retinal plexus, and evaluated the extent of the non-flow area and the foveal avascular zone (FAZ) on a 3 × 3 mm macular region. Kruskal-Wallis test was performed for statistical analysis. RESULTS: In Group AMD 20x, the vascular density of superficial retinal plexus in the fovea (p = 0.0022) and parafovea (p < 0.0001) was significantly lower compared to Group one year and control group. In the deep retinal plexus, vascular density in the fovea (p = 0.0033) was significantly lower in both AMD groups compared to the control group, with no difference in the parafoveal region (p = 0.0774). The extent of non-flow area (p = 0.0003) and FAZ (p = 0.0008) were significantly larger in both AMD groups compared to the control group. There was a significant difference in CRT between those treated for one year and control eyes (p = 0.0036). CONCLUSIONS: In our study, we demonstrated that macular vessel density was lower in the foveal area in the superficial retinal plexus in AMD patients after one year and long-term anti-VEGF treatment. These vascular density changes were absent in the parafoveal and whole areas of the deep retinal plexus. Our results indicate that long-term anti-VEGF treatment reduces the vascular density of the superficial retinal plexus to a greater extent compared to the deep retinal plexus.
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Degeneração Macular , Vasos Retinianos , Humanos , Angiofluoresceinografia/métodos , Estudos Transversais , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Inibidores da Angiogênese , Injeções Intravítreas , Degeneração Macular/patologia , Atrofia/patologia , Estudos RetrospectivosRESUMO
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 , Fotografação , Fundo de Olho , Humanos , Fotografação/métodos , Projetos Piloto , Reprodutibilidade dos TestesRESUMO
PURPOSE: There is abundant evidence on the benefits of physical activity on cardiovascular health. However, there are only few data on the acute effects of physical exercise on the retina and choroid. Our aim was the in vivo examination of chorioretinal alterations following short intense physical activity by spectral domain optical coherence tomography (SD-OCT). METHODS: Twenty-one eyes of 21 healthy, young subjects (mean age 22.5 ± 4.1 years, 15 males and 6 females) were recruited. Macular scanning with a SD-OCT was performed before and following a vita maxima-type physical strain exercise on a rowing ergometer until complete fatigue. Follow-up OCT scans were performed 1, 5, 15, 30 and 60 minutes following the exercise. The OCT images were exported and analyzed using our custom-built OCTRIMA 3D software and the thickness of 7 retinal layers was calculated, along with semi-automated measurement of the choroidal thickness. One-way ANOVA analysis was performed followed by Dunnett post hoc test for the thickness change compared to baseline and the correlation between performance and thickness change has also been calculated. The level of significance was set at 0.001. RESULTS: We observed a significant thinning of the total retina 1 minute post-exercise (-7.3 ± 0.6 µm, p < 0.001) which was followed by a significant thickening by 5 and 15 minutes (+3.6 ± 0.6 µm and +4.0 ± 0.6 µm, respectively, both p <0.001). Post-exercise retinal thickness returned to baseline by 30 minutes. This trend was present throughout the most layers of the retina, with significant changes in the ganglion cell-inner plexiform layer complex, (-1.3 ± 0.1 µm, +0.6 ± 0.1 µm and +0.7 ± 0.1 µm, respectively, p <0.001 for all), in the inner nuclear layer at 1 and 5 minutes (-0.8 ± 0.1 µm and +0.8 ± 0.1 µm, respectively, p <0.001 for both), in the outer nuclear layer-photoreceptor inner segment complex at 5 minute (+2.3 ± 0.4 µm, p <0.001 for all) and in the interdigitation zone-retinal pigment epithelium complex at 1 and 15 minutes (-3.3 ± 0.4 µm and +1.8 ± 0.4 µm, respectively, p <0.001 for both). There was no significant change in choroidal thickness; however, we could detect a tendency towards thinning at 1, 15, and 30 minutes following exercise. The observed changes in thickness change did not correlate with performance. Similar trends were observed in both professional and amateur sportsmen (n = 15 and n = 6, respectively). The absolute changes in choroidal thickness did not show any correlation with the thickness changes of the intraretinal layers. CONCLUSIONS: Our study implies that in young adults, intense physical exercise has an acute effect on the granular layers of the retina, resulting in thinning followed by rebound thickening before normalization. We could not identify any clear correlation with either choroidal changes or performance that might explain our observations, and hence the exact mechanism warrants further clarification. We believe that a combination of vascular and mechanic changes is behind the observed trends.
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Corioide , Tomografia de Coerência Óptica , Adolescente , Adulto , Corioide/irrigação sanguínea , Corioide/diagnóstico por imagem , Exercício Físico , Feminino , Humanos , Masculino , Retina/diagnóstico por imagem , Epitélio Pigmentado da Retina , Tomografia de Coerência Óptica/métodos , Adulto JovemRESUMO
OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
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Projetos de Pesquisa , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica , Consenso , Técnica Delphi , Humanos , Oftalmologia/métodosRESUMO
INTRODUCTION: Ocular blood flow plays a critical role in eye health by nourishing the retinal and ocular tissues with oxygen and nutrients and removal of ocular metabolic waste. Imaging of retinal and optic blood flow may provide insights for early and more specific diagnoses of ocular vascular disorder and facilitate eye-based biomarkers applicable to neurological health assessment and research. AREAS COVERED: The ability of the XyCAM RI (Vasoptic Medical Inc., MD, USA) to visualize and to analyze ocular blood flow dynamics XyCAM RI using laser speckle contrast imaging is reviewed and compared with concurrent clinical ophthalmic imaging technologies like optical coherence tomography - angiography (OCT-A), fundus imaging, fluorescein angiography (FA), indocyanine green angiography (ICGA), laser Doppler flowmetry (LDF), and laser speckle flowgraphy (LSFG). EXPERT OPINION: XyCAM RI, with its unprecedented imaging capabilities to assess blood flow dynamics provides a powerful tool to ophthalmic researchers and doctors to obtain greater clinical insights into the physiological status of the posterior segment and treatment approaches for various diseases in a very patient-friendly, noninvasive manner, unlike dye-based angiographic techniques such as FA or ICG. XyCAM RI is well suited as a modality that could close the gap between current screening and comprehensive eye exams.
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Fluxo Sanguíneo Regional/fisiologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/fisiologia , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Humanos , Reprodutibilidade dos Testes , Doenças Retinianas/diagnóstico , Doenças Retinianas/diagnóstico por imagemRESUMO
AIM: To evaluate a high-resolution functional imaging device that yields quantitative data regarding macular blood flow and capillary network features in eyes with diabetic retinopathy (DR). METHODS: Prospective, cross-sectional comparative case-series in which blood flow velocities (BFVs) and non-invasive capillary perfusion maps (nCPMs) in macular vessels were measured in patients with DR and in healthy controls using the Retinal Functional Imager (RFI) device. RESULTS: A total of 27 eyes of 21 subjects were studied [9 eyes nonproliferative diabetic retinopathy (NPDR), 9 eyes proliferative diabetic retinopathy (PDR) and 9 controls]. All diabetic patients were type 2. All patients with NPDR and 5 eyes with PDR also had diabetic macular edema (DME). The NPDR group included eyes with severe (n=3) and moderate NPDR (n=6), and were symptomatic. A significant decrease in venular BFVs was observed in the macular region of PDR eyes when compared to controls (2.61±0.6 mm/s and 2.92±0.72 mm/s in PDR and controls, respectively, P=0.019) as well as PDR eyes with DME compared to NPDR eyes (2.36±0.51 mm/s and 2.94±1.09 mm/s in PDR with DME and NPDR, respectively, P=0.01). CONCLUSION: The RFI, a non-invasive imaging tool, provides high-resolution functional imaging of the retinal microvasculature and quantitative measurement of BFVs in visually impaired DR patients. The isolated diminish venular BFVs in PDR eyes compared to healthy eyes and PDR eyes with DME in comparison to NPDR eyes may indicate the possibility of more retinal vein compromise than suspected in advanced DR.
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In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
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Doença de Alzheimer/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico por imagem , Retina/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Encéfalo/diagnóstico por imagem , Humanos , Pessoa de Meia-IdadeRESUMO
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/irrigação sanguínea , Vasos Retinianos/diagnóstico por imagem , Gravação em Vídeo/instrumentação , Adulto , Equipamentos e Provisões , Feminino , Angiofluoresceinografia , Voluntários Saudáveis , Hemodinâmica , Humanos , Masculino , Disco Óptico/diagnóstico por imagem , Fluxo Sanguíneo Regional , Tomografia de Coerência ÓpticaRESUMO
INTRODUCTION: We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross-validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD. METHODS: The proposed minimum data set framework is based on the Atlas of Retinal Imaging Study (ARIAS), an ongoing, longitudinal, multi-site observational cohort study. However, the ARIAS protocol has been edited and refined with the expertise of all co-authors, representing 16 institutions, and research groups from three countries, as a first step to address a pressing need identified by experts in neuroscience, neurology, optometry, and ophthalmology at the Retinal Imaging in Alzheimer's Disease (RIAD) conference, convened by the Alzheimer's Association and held in Washington, DC, in May 2019. RESULTS: Our framework delineates specific imaging protocols and methods of analysis for imaging structural changes in retinal neuronal layers, with optional add-on procedures of fundus autofluorescence to examine beta-amyloid accumulation and optical coherence tomography angiography to examine AD-related changes in the retinal vasculature. DISCUSSION: This minimum data set represents a first step toward the standardization of retinal imaging data acquisition and analysis in cognitive aging and AD. A standardized approach is essential to move from discovery to validation, and to examine which retinal AD biomarkers may be more sensitive and specific for the different stages of the disease severity spectrum. This approach has worked for other biomarkers in the AD field, such as magnetic resonance imaging; amyloid positron emission tomography; and, more recently, blood proteomics. Potential context of use for retinal AD biomarkers is discussed.
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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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The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.