Da Vitoria Lobo, Marlene Elisa; (2024) An Automated Toolkit for Vascular Morphology And Pericyte Characteristic Analysis In Early Diabetic Retinopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Diabetic retinopathy (DR) is a leading cause of blindness worldwide. It is typically diagnosed through visible vascular changes but is preceded by subtle, early alterations that current clinical methods often miss. Early detection of these changes is crucial to prevent significant vision loss. Preclinical models, like diabetic rodent models and confocal microscopy, are invaluable for studying these early changes. However, traditional manual analysis of these alterations is labour-intensive and subject to bias, often focusing separately on vascular or pericyte changes and missing their crucial interplay. To address this, we developed an automated tool capable of simultaneously examining both vascular and pericyte alterations in murine retinal confocal images. First, we established a framework for the automated analysis of retinal vascular morphology, focusing on metrics such as vessel length, width, and tortuosity. We then created a meticulously annotated dataset of pericytes and pericyte bridges from confocal images and trained deep learning models using YOLOv5s to automatically identify various pericyte types, eliminating manual counting. We applied these tools to characterise changes in retinal vessels and pericytes in an Streptozotocin (STZ)-induced diabetic mouse model. Analysing over three time points (8, 16, and 24 weeks), we found significant vessel elongation and reduced branching at 16 and 24 weeks, likely due to capillary drop-out from 8 chronic hyperglycaemia. Vessel widths varied, with a notable reduction at 16 weeks, tortuosity increased at 24 weeks suggesting adaptive morphological alterations in response to initial structural changes. We also observed an increase in the formation of pericyte bridges and a decrease in attached pericytes, indicating a dynamic imbalance. We then performed spatial analysis and at 24 weeks, we saw an increase in tortuosity in vessels associated with pericyte bridges concurrent with an upregulated Lrg1 expression which pointed to ongoing vascular remodelling under chronic hyperglycaemia. Our dual analysis bridges changes in morphology and pericyte behaviour, with the underlying molecular mechanisms driving these alterations, enhancing our understanding of the pathological progression of DR.

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