Fractal-based analysis of optical coherence tomography data to quantify retinal tissue damage

BACKGROUND: The sensitivity of Optical Coherence Tomography (OCT) images to identify retinal tissue morphology characterized by early neural loss from normal healthy eyes is tested by calculating structural information and fractal dimension. OCT data from 74 healthy eyes and 43 eyes with type 1 diabetes mellitus with mild diabetic retinopathy (MDR) on biomicroscopy was analyzed using a custom-built algorithm (OCTRIMA) to measure locally the intraretinal layer thickness. A power spectrum method was used to calculate the fractal dimension in intraretinal regions of interest identified in the images. ANOVA followed by Newman-Keuls post-hoc analyses were used to test for differences between pathological and normal groups. A modified p value of <0.001 was considered statistically significant. Receiver operating characteristic (ROC) curves were constructed to describe the ability of each parameter to discriminate between eyes of pathological patients and normal healthy eyes. RESULTS: Fractal dimension was higher for all the layers (except the GCL + IPL and INL) in MDR eyes compared to normal healthy eyes. When comparing MDR with normal healthy eyes, the highest AUROC values estimated for the fractal dimension were observed for GCL + IPL and INL. The maximum discrimination value for fractal dimension of 0.96 (standard error =0.025) for the GCL + IPL complex was obtained at a FD <= 1.66 (cut off point, asymptotic 95% Confidence Interval: lower-upper bound = 0.905-1.002). Moreover, the highest AUROC values estimated for the thickness measurements were observed for the OPL, GCL + IPL and OS. Particularly, when comparing MDR eyes with control healthy eyes, we found that the fractal dimension of the GCL + IPL complex was significantly better at diagnosing early DR, compared to the standard thickness measurement. CONCLUSIONS: Our results suggest that the GCL + IPL complex, OPL and OS are more susceptible to initial damage when comparing MDR with control healthy eyes. Fractal analysis provided a better sensitivity, offering a potential diagnostic predictor for detecting early neurodegeneration in the retina

Reflections on the Utility of the Retina as a Biomarker for Alzheimer's Disease: A Literature Review.

As a part of the central nervous system, the retina may reflect both physiologic processes and abnormalities related to diseases of the brain. Indeed, a concerted effort has been put forth to understand how Alzheimer's disease (AD) pathology may manifest in the retina as a means to assess the state of the AD brain. The development and refinement of ophthalmologic techniques for studying the retina in vivo have produced evidence of retinal degeneration in AD diagnosed patients. In this review, we will discuss retinal imaging techniques implemented to study the changes in AD retina as well as highlight the recent efforts made to correlate such findings to other clinical hallmarks of AD to assess the viability of the retina as a biomarker for AD

Retinal Imaging in Alzheimer’s Disease

Identifying biomarkers of Alzheimer's disease (AD) will accelerate the understanding of its pathophysiology, facilitate screening and risk stratification, and aid in developing new therapies. Developments in non-invasive retinal imaging technologies, including optical coherence tomography (OCT), OCT angiography and digital retinal photography, have provided a means to study neuronal and vascular structures in the retina in people with AD. Both qualitative and quantitative measurements from these retinal imaging technologies (eg, thinning of peripapillary retinal nerve fibre layer, inner retinal layer, and choroidal layer, reduced capillary density, abnormal vasodilatory response) have been shown to be associated with cognitive function impairment and risk of AD. The development of computer algorithms for respective retinal imaging methods has further enhanced the potential of retinal imaging as a viable tool for rapid, early detection and screening of AD. In this review, we present an update of current retinal imaging techniques and their potential applications in AD research. We also discuss the newer retinal imaging techniques and future directions in this expanding field

On the Indeterminates of Glaucoma:the Controversy of Arterial Blood Pressure and Retinal Perfusion

Glaucoma is a chronic eye disease characterized by thinning of the retina, death of ganglion cells, and progressive loss of vision, eventually leading to blindness. The prevalence of glaucoma is estimated at 1-3% of those over 40 years old. With a constantly aging population, this number is expected to increase significantly over the next 10 years. Even with treatment, about 15% of people with glaucoma currently develop residual vision or tunnel vision and eventually become blind or partially sighted. The mechanisms behind ganglion cell death are poorly understood. Elevated eye pressure is the main risk factor for glaucoma, but treatment in the form of medication, laser, or surgery can only slow the decline, not stop it. In addition, high intraocular pressure is neither necessary nor sufficient for the development of glaucoma, indicating the existence of other unknown risk factors. It has been established that the death of ganglion cells results in a decreased oxygen demand and a concomitant decrease in blood flow. However, there is also a hypothesis that reduced or unstable blood supply is not only a consequence, but also a cause of glaucoma. This is known as the ‘chicken-egg’ dilemma in glaucoma. It is supported by the observation that the risk of developing glaucoma is higher in people with very low blood pressure (sometimes even as a result of overtreatment of high blood pressure).This dissertation is an attempt to methodically examine whether blood pressure can be linked to changes in the retina that could suggest susceptibility to glaucoma. For this purpose, we analyze epidemiological data from the Groningen Longitudinal Glaucoma Study, we use advanced imaging techniques to model the microcirculation, and we describe its relationship with the neural structure and oxygen consumption of the retina. We provide evidence leaning towards the existence of a vascular component, likely pertinent to glaucoma

Investigating Tissue Optical Properties and Texture Descriptors of the Retina in Patients with Multiple Sclerosis

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

Microcirculatory model predicts blood flow and autoregulation range in the human retina:in vivo investigation with laser speckle flowgraphy

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained float 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregula tion limits (LARL/HARL), using retinal vessel calibers, fractal dimen- sion, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R-2 =0.77/P = 6.9.10(-9)) and RBF (R-2 =0.65/P = 1.0.10(-6)), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0.10(-4)) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies. NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops

Quantitative Optical Studies of Oxidative Stress in Rodent Models of Eye and Lung Injuries

Optical imaging techniques have emerged as essential tools for reliable assessment of organ structure, biochemistry, and metabolic function. The recognition of metabolic markers for disease diagnosis has rekindled significant interest in the development of optical methods to measure the metabolism of the organ. The objective of my research was to employ optical imaging tools and to implement signal and image processing techniques capable of quantifying cellular metabolism for the diagnosis of diseases in human organs such as eyes and lungs. To accomplish this goal, three different tools, cryoimager, fluorescent microscope, and optical coherence tomography system were utilized to study the physiological metabolic markers and early structural changes due to injury in vitro, ex vivo, and at cryogenic temperatures. Cryogenic studies of eye injuries in animal models were performed using a fluorescence cryoimager to monitor two endogenous mitochondrial fluorophores, NADH (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). The mitochondrial redox ratio (NADH/ FAD), which is correlated with oxidative stress level, is an optical biomarker. The spatial distribution of mitochondrial redox ratio in injured eyes with different durations of the disease was delineated. This spatiotemporal information was helpful to investigate the heterogeneity of the ocular oxidative stress in the eyes during diseases and its association with retinopathy. To study the metabolism of the eye tissue, the retinal layer was targeted, which required high resolution imaging of the eye as well as developing a segmentation algorithm to quantitatively monitor and measure the metabolic redox state of the retina. To achieve a high signal to noise ratio in fluorescence image acquisition, the imaging was performed at cryogenic temperatures, which increased the quantum yield of the intrinsic fluorophores. Microscopy studies of cells were accomplished by using an inverted fluorescence microscope. Fixed slides of the retina tissue as well as exogenous fluorophores in live lung cells were imaged using fluorescent and time-lapse microscopy. Image processing techniques were developed to quantify subtle changes in the morphological parameters of the retinal vasculature network for the early detection of the injury. This implemented image cytometry tool was capable of segmenting vascular cells, and calculating vasculature features including: area, caliber, branch points, fractal dimension, and acellular capillaries, and classifying the healthy and injured retinas. Using time-lapse microscopy, the dynamics of cellular ROS (Reactive Oxygen Species) concentration was quantified and modeled in ROS-mediated lung injuries. A new methodology and an experimental protocol were designed to quantify changes of oxidative stress in different stress conditions and to localize the site of ROS in an uncoupled state of pulmonary artery endothelial cells (PAECs). Ex vivo studies of lung were conducted using a spectral-domain optical coherence tomography (SD-OCT) system and 3D scanned images of the lung were acquired. An image segmentation algorithm was developed to study the dynamics of structural changes in the lung alveoli in real time. Quantifying the structural dynamics provided information to diagnose pulmonary diseases and to evaluate the severity of the lung injury. The implemented software was able to quantify and present the changes in alveoli compliance in lung injury models, including edema. In conclusion, optical instrumentation, combined with signal and image processing techniques, provides quantitative physiological and structural information reflecting disease progression due to oxidative stress. This tool provides a unique capability to identify early points of intervention, which play a vital role in the early detection of eye and lung injuries. The future goal of this research is to translate optical imaging to clinical settings, and to transfer the instruments developed for animal models to the bedside for patient diagnosis

Application of ImageJ in Optical Coherence Tomography Angiography (OCT-A): A Literature Review

Background. This study aimed to review the literature on the application of ImageJ in optical coherence tomography angiography (OCT-A) images. Methods. A general search was performed in PubMed, Google Scholar, and Scopus databases. The authors evaluated each of the selected articles in order to assess the implementation of ImageJ in OCT-A images. Results. ImageJ can aid in reducing artifacts, enhancing image quality to increase the accuracy of the process and analysis, processing and analyzing images, generating comparable parameters such as the parameters that assess perfusion of the layers (vessel density (VD), skeletonized density (SD), and vessel length density (VLD)) and the parameters that evaluate the structure of the layers (fractal dimension (FD), vessel density index (VDI), and lacunarity (LAC)), and the foveal avascular zone (FAZ) that are used widely in the retinal and choroidal studies), and establishing diagnostic criteria. It can help to save time when the dataset is huge with numerous plugins and options for image processing and analysis with reliable results. Diverse studies implemented distinct binarization and thresholding techniques, resulting in disparate outcomes and incomparable parameters. Uniformity in methodology is required to acquire comparable data from studies employing diverse processing and analysis techniques that yield varied outcomes. Conclusion. Researchers and professionals might benefit from using ImageJ because of how quickly and correctly it processes and analyzes images. It is highly adaptable and potent software, allowing users to evaluate images in a variety of ways. There exists a diverse range of methodologies for analyzing OCTA images through the utilization of ImageJ. However, it is imperative to establish a standardized strategy to ensure the reliability and consistency of the method for research purposes

The Retinal Microvasculature in Secondary Progressive Multiple Sclerosis

In light of new data regarding pathology of multiple sclerosis (MS), more research is needed into the vascular aspects of the disease. Demyelination caused by inflammation is historically thought of as the main cause of disability in the disease. Recent studies, however, have suggested that MS is in fact a spectrum of overlapping phenotypes consisting of inflammation, oxidative damage and hypoperfusion. The microvasculature plays an important role in all of these pathogenic processes and its dysfunction may therefore be of crucial importance to the development and progression of the disease. This thesis focuses on investigating the microvasculature of the retina as a surrogate for the brain by assessing the vascular structure, blood flow dynamics and oxygen transfer of the retinal blood vessels in secondary progressive multiple sclerosis (SPMS). Studying the retinal microvasculature using a multimodal imaging approach has allowed us to develop a more detailed understanding of blood flow in MS and to identify new imaging markers for trials into neuroprotective drugs in MS. The work done in this thesis demonstrated; i) a higher rate of retinal microvascular abnormalities in MS which progresses with disease severity, ii) evidence of retinal vascular remodelling in SPMS and iii) changes in blood velocity and flow in the retina in SPMS. These observations pave the way for future investigations into the mechanisms of vascular alterations and vascular dysfunction in MS, and provide a set of imaging markers to further explore other cerebrovascular diseases through the retina