RETINAL IMAGING IN CEREBROVASCULAR DISEASE AND DEMENTIA

Ph.DDOCTOR OF PHILOSOPH

RETINAL AND CEREBRAL NEUROIMAGING BIOMARKERS FOR COGNITIVE IMPAIRMENT

Ph.DDOCTOR OF PHILOSOPH

Retinal Vascular Measurement Tools for Diagnostic Feature Extraction

The contributions of this work are in the development of new and state of the art algorithms for retinal image analysis including optic disc detection, tortuosity estimation, and cross-over abnormality detection. The retina is one of the only areas of the human body that blood vessels can be visualized noninvasively. Retinal imaging has become a standard in the ophthalmologist’s office because it is an easy and inexpensive way to monitor not just eye health, but also systemic vascular diseases. Changes to the retinal vasculature can be the early signs of diseases such as diabetic and hypertensive retinopathy, of which early detection can save vision, money, and improve overall health for the patient. When looking at the retinal vasculature, ophthalmologists generally rely on a qualitative assessment which can make comparisons over time or between different ophthalmologists difficult. Computer aided systems are now able to quantify what the ophthalmologist is qualitatively measuring in what they consider to be the most important features of the vasculature. These include, but are not limited to, tortuosity, arteriolar narrowing, cross-over abnormalities, and artery-vein (AV) ratio. The University of Padova has created a semi-automatic system for detecting and quantifying retinal vessels starting from optic disc detection, vessel segmentation, width estimation, tortuosity calculation, AV classification, and AV ratio. We propose a new method for optic disc detection that converts the retinal image into a graph and exploits vessel enhancement methods to calculate edge weights in finding the shortest path between pairs of points on the periphery of the image. The line segment with the maximum number of shortest paths is considered the optic disc location. The method was tested on three publicly available datasets: DRIVE, DIARETDB1, and Messidor consisting of 40, 89, and 1200 images and achieved an accuracy of 100, 98.88, and 99.42% respectively. The second contribution is a new algorithm for calculating abnormalities at AV crossing points. In retinal images, Gunn’s sign appears as a tapering of the vein at a crossing point, while Salus’s sign presents as an S-shaped curving. This work presents a method for the automatic quantification of these two signs once a crossover has been detected; combining segmentation, artery vein classification, and morphological feature extraction techniques to calculate vein widths and angles entering and exiting the crossover. Results on two datasets show separation between the two classes and that we can reliably detect and quantify these signs under the right conditions. The last contribution in tortuosity consists of two parts. A comparative study was performed on several of the most popular methods for tortuosity estimation on a new vessel dataset. Results show that several methods have good Cohen’s kappa agreement with both graders, while the tortuosity density metric has the highest single metric average agreement across vessel type and grader. The second is a new way to enhance curvature in segmented vessels based on a difference of Gabor filters to create a curvature enhanced image. The proposed method was tested on the RET-TORT database using several methods to calculate tortuosity, and had best Pearson’s correlation of .94 for arteries and .882 for veins, outperforming single mathematical formulations on the data. This held true after testing the method on the propose dataset as well, having higher correlation values across grader and vessel type compared with other tortuosity metrics. Summary of Results: The optic disc detection method was tested on three publicly available datasets: DRIVE, DIARETDB1, and Messidor consisting of 40, 89, and 1200 images and achieved an accuracy of 100, 98.88, and 99.42% respectively. The AV nicking quantification method was tested on a small dataset of 10 crossing provided by doctors at Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Results showed separation between the normal and abnormal classes for both the Gunn and Salus sign. The method was then tested on a larger, publicly available dataset which showed good separation for the Gunn sign. The proposed tortuosity method was tested on the RET-TORT database using several methods to calculate tortuosity, and had best Pearson’s correlation of .94 for arteries and .882 for veins, outperforming single mathematical formulations on the data. It was then tested on the dataset proposed in this thesis, further corroborating the effectiveness of the method

Digital ocular fundus imaging: a review

Ocular fundus imaging plays a key role in monitoring the health status of the human eye. Currently, a large number of imaging modalities allow the assessment and/or quantification of ocular changes from a healthy status. This review focuses on the main digital fundus imaging modality, color fundus photography, with a brief overview of complementary techniques, such as fluorescein angiography. While focusing on two-dimensional color fundus photography, the authors address the evolution from nondigital to digital imaging and its impact on diagnosis. They also compare several studies performed along the transitional path of this technology. Retinal image processing and analysis, automated disease detection and identification of the stage of diabetic retinopathy (DR) are addressed as well. The authors emphasize the problems of image segmentation, focusing on the major landmark structures of the ocular fundus: the vascular network, optic disk and the fovea. Several proposed approaches for the automatic detection of signs of disease onset and progression, such as microaneurysms, are surveyed. A thorough comparison is conducted among different studies with regard to the number of eyes/subjects, imaging modality, fundus camera used, field of view and image resolution to identify the large variation in characteristics from one study to another. Similarly, the main features of the proposed classifications and algorithms for the automatic detection of DR are compared, thereby addressing computer-aided diagnosis and computer-aided detection for use in screening programs.Fundação para a Ciência e TecnologiaFEDErPrograma COMPET

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

Vessel labeling in combined confocal scanning laser ophthalmoscopy and optical coherence tomography Images : criteria for blood vessel discrimination

INTRODUCTION: The diagnostic potential of optical coherence tomography (OCT) in neurological diseases is intensively discussed. Besides the sectional view of the retina, modern OCT scanners produce a simultaneous top-view confocal scanning laser ophthalmoscopy (cSLO) image including the option to evaluate retinal vessels. A correct discrimination between arteries and veins (labeling) is vital for detecting vascular differences between healthy subjects and patients. Up to now, criteria for labeling (cSLO) images generated by OCT scanners do not exist. OBJECTIVE: This study reviewed labeling criteria originally developed for color fundus photography (CFP) images. METHODS: The criteria were modified to reflect the cSLO technique, followed by development of a protocol for labeling blood vessels. These criteria were based on main aspects such as central light reflex, brightness, and vessel thickness, as well as on some additional criteria such as vascular crossing patterns and the context of the vessel tree. RESULTS AND CONCLUSION: They demonstrated excellent inter-rater agreement and validity, which seems to indicate that labeling of images might no longer require more than one rater. This algorithm extends the diagnostic possibilities offered by OCT investigations

Automatic computation of the arteriovenous ratio and assessment of its effectiveness as a prognostic indicator in hypertension

[Resumen] La retina es la única parte del cuerpo humano en donde se pueden observar los vasos sanguíneos directamente de una forma no invasiva mediante un examen de fondo de ojo. De esta manera, la imagen de la retina mediante las técnicas de procesamiento de imágenes se convirtió en un campo de clave para el diagnóstico precoz de varias enfermedades sistémicas que provocan alteraciones visibles en dicha imagen. Así, alteraciones en el ancho de los vasos retinianos se asocian con patologías tales como diabetes o hipertensión. De hecho, el estrechamiento de las arterias constituye un indicio precoz de la hipertensión arterial sistémica, siendo una característica del grado I de la retinopatía hipertensiva de acuerdo con la clasificación de Keith-Wagener-Barker. En este sentido, se han realizado esfuerzos para desarrollar programas asistidos por ordenador para medir con precisión los cambios en el ancho de los vasos a través del índice arteriovenoso (IAV), es decir, la relación entre los calibres de las arterias y las venas. Sin embargo, aunque estos sistemas se han usado en muchos estudios con fines de investigación, su aplicabilidad en la práctica clínica diaria es todavía discutida. En este trabajo, se propone una nueva metodología para el cálculo del IAV con el fin de estratificar el riesgo cardiovascular de los hipertensos. Por un lado, se ha desarrollado un método completamente automático para estimar el IAV en una imagen de fondo de ojo de un paciente. Por otro lado, se propone un sistema para monitorizar el IAV del paciente a lo largo del tiempo. Para este fin, las mediciones del IAV en las diferentes imágenes adquiridas sobre el mismo ojo del paciente en diferentes fechas se estiman usando el mismo conjunto de vasos medidos en las mismas áreas. Por lo tanto, la mediciones obtenidos de esta manera son comparables y precisas, debido a que son independientes en el conjunto de vasos seleccionados para el cálculo. Las dos técnicas se han integrado en SIRIUS, un sistema web destinado a incluir diferentes servicios en el campo del análisis de la imagen retiniana. El sistema incluye también gestión de pacientes y revisiones, lo que facilita el análisis de las lesiones retinianas causadas por diferentes patologías y su evolución después de un determinado tratamiento. Además al ser una aplicación distribuída a través de la web, proporciona un entorno de colaboración entre diferentes médicos, investigadores y centros.[Resumo] A retina é a única parte do corpo humano onde se poden observar os vasos sanguíneos directamente dunha maneira non invasiva mediante un examen do fondo do ollo. Desta maneira, a imaxe da retina mediante as técnicas de procesamento de imáxenes converteuse nun campo chave para o diagnóstico precoz de varias enfermidades sistémicas que provocan alteracións visibles en dita imaxe. Así, cambios no ancho dos vasos retinianos asócianse con patoloxías tales como a diabetes ou a hipertensión. De feito, o estreitamento das arterias constitúe un indicio prematuro da hipertensión arterial sistémica, sendo unha característica do grado I da retinopatía hipertensiva dacordo coa clasificación de Keith- Wagener-Barker. Neste sentido, fixerónse moitos esforzos para desenvolver programas asistidos por ordenador para medir con precisión os cambios no ancho dos vasos a través do índice arteriovenoso (IAV), é dicir, a relación entre os calibres das arterias e das veas. Nembargantes, aínda que estes sistemas foron usados en moitos estudios con fins investigadores, a sua aplicabilidade na práctica clínica diaria aínda é discutida. Neste traballo, proponse unha nova metodoloxía para o cálculo do IAV co fin de estratificar o risco cardiovascular dos hipertensos. Por un lado, desenvolveuse un método completamente automático para estimar o IAV nunha imaxe de fondo de ollo dun doente. Por outra banda, proponse un sistema para monitorizar o IAV dun doente a lo longo do tempo. Para isto, as medicións do IAV nas diferentes imaxes adquiridas sobre o mesmo ollo do doente en diferentes datas fanse usando o mesmo conxunto de vasos medidos nas mesmas áreas. Polo tanto, as medicións obtidas desta maneira son comparables e precisas, debido a que son independentes do conxunto de vasos seleccionados para o cálculo. As dúas técnicas foron integradas no SIRIUS, un sistema web destinado a incluir diferentes servicios no campo da análise da imaxe retiniana. O sistema inclúe tamén xestión de doentes e revisións, facilitando a análise e estudo das lesións retinianas causadas por diferentes patoloxías e a súa evolución despois dun determinado tratamento. Ademais ao ser unha aplicación distribuída a través da web, proporciona un entorno de colaboración entre diferentes médicos, investigadores e centros.[Abstract] Retina is the only part in the human body where blood vessels can be directly observed in a non-invasive way through an eye fundus examination. In this manner, the retinal imaging assisted by image processing techniques became a key field for the early diagnosis of several systemic diseases which cause visible alterations in the fundus image. Thus, changes in the retinal vessel widths are associated with pathologies such as diabetes or hypertension. In fact, arteriolar narrowing constitutes an early sign of systemic hypertension, being a feature for the grade I of hypertension retinopathy according to Keith-Wagener-Barker classification. In this sense, some efforts have been made to develop computer-assisted programs to measure accurately abnormalities in the vessel widths through the arteriovenous ratio (AVR), that is, the relation between arteriolar and venular vessel widths. However, although these systems have been used in many studies for research purposes, their applicability to daily clinical practice is yet discussed. In this work, a new methodology for the AVR computation is proposed in order to stratify the cardiovascular risk of hypertension. On one hand, a fully automatic method to estimate the AVR in a sample patient's image is developed. On the other hand, an AVR monitoring system to compute the patient's AVR over time was implemented. To this end, the AVR measurements computed in the different patient's images acquired from the same eye at different dates, uses the same set of vessels measured at the same areas. Thus, the measurements achieved in this manner are comparable and precise due to they are independent on the set of vessels selected for the calculus. The two approaches have been integrated in SIRIUS, a web-based system aimed to include different services in the field of retinal image analysis. It includes patient and checkup management, making easier to analyze the retinal lesions caused by different pathologies and their evolution after a specific treatment. Moreover, being a application distributed via the web, it provides a collaborative environment among different physicians, researchers and medical centers