iCase: Developing computational analysis of ultra-widefield fluorescein angiography of the retina to gain personalised...

MRC’s iCASE awards provide students with experience of collaborative research with a non academic partner, enabling the student to spend a period of time with the non-academic partner (usually no less than three months over the lifetime of the PhD).

Students who are successfully awarded an iCASE studentship are entitled to an additional £2,500 per year as a supplement to their stipend and an annual cash contribution of at least £1,400 towards the cost of the project.  The iCase project additional funding is only secured once contracts between the industrial partner and University of Edinburgh are signed. 

Background

Cerebral small vessel disease (cSVD) affects the brain’s microvasculature and is a major contributor to stroke, dementia, and other neurological impairments [1]. A hallmark of cSVD is excessive blood–brain barrier permeability, which allows harmful substances to enter the brain via ‘leaky’ vessels, triggering inflammation and tissue damage [2]. Despite its clinical significance, our understanding of cSVD and vascular permeability remains limited, partly because conventional imaging techniques (such as MRI and CT) lack the spatial resolution to directly visualise small vessels in vivo [3]. Instead, these modalities detect secondary consequences of microvascular dysfunction in the brain like tissue injury or fluid accumulation.

The microvasculature of the retina closely reflects the structural and functional properties of small cerebral vessels [4]. Retinovascular permeability can be directly assessed using fluorescein angiography that involves intravenous injection of a fluorescent dye and imaging the back of the eye with a scanning laser ophthalmoscope. The laser excites or lights up the dye as it travels through the retinal vessels enabling visualisation of any vascular leakage. Devices made by Optos (our industry partner) are particularly suited to this work as they provide ultra-widefield views that include the far retinal periphery, an anatomical region that appears to be particularly susceptible to leakage.

Investigating retinal permeability in this way could offer a non-invasive window into microvascular integrity, with potential to yield valuable insights into cSVD. This in turn would support the development of targeted therapeutic interventions for individuals with impaired vascular function and provide a scalable biomarker for monitoring treatment efficacy in clinical populations. 

Aims

The student will join our group, which specialises in developing computational pipelines for analysing retinal images and their application to ocular, systemic, and neurological diseases. Together with Optos providing specialist guidance in their imaging, the student will leverage the expertise of the team to develop cutting-edge image analysis techniques and extract clinically meaningful measures from fluorescein angiography that inform brain health.

In undertaking the project, the student will:

1. Design and implement computational methods to efficiently and reliably quantify retinal vessel leakage and capillary non-perfusion from fluorescein angiography.
2. Apply these novel analytical techniques along with existing ones that measure other key retinal features (e.g., vessels, optic nerve) to identify and compare patterns across distinct patient cohorts.
3. Examine associations between retinal leakage and MRI markers of cSVD, additional indicators of neurovascular dysfunction and neurodegeneration in the retina, and clinical markers of health.
4. Assess longitudinal changes within individuals (i.e., MRI measured progression, retinal nerve fibre layer thinning, and cognitive decline) to support personalised profiling of vascular brain health.
5. Explore translational routes for integrating these technologies into clinical and commercial settings.

The project benefits from access to an existing patient cohort (n=43) comprising individuals who have suffered a mild stroke, have cSVD, and for whom fluorescein angiography imaging and MRI brain have already been acquired. These participants will be invited for repeat imaging 12-24 months from now. In addition, we will conduct retinal imaging in a mid-life cohort (n=130) currently in good health but at elevated risk for late-life dementia and thus some may exhibit early signs of cSVD. For all participants, we have comprehensive data including MRI-derived markers of cSVD, detailed structural and vascular retinal measurements, risk factors for stroke and dementia, and cognitive assessments. Ultra-widefield fluorescein angiography images from normal eyes will be provided by Optos, and allow comparison of our patient cohorts against an external control group. In addition to cSVD, methods developed through this project will be directly relevant to several sight-threatening conditions, such as posterior uveitis, retinal vein occlusion, and diabetic retinopathy.

Training outcomes

Project-specific training/experience will be provided in:

1. Retinal imaging and brain MRI
2. Computational image analysis
3. Brain health, stroke, and dementia
4. Machine learning-based and statistical methods for cross-sectional and longitudinal image/data analysis

References

1. Ter Telgte A, Duering M. Cerebral Small Vessel Disease: Advancing Knowledge With Neuroimaging. Stroke. 2024 Jun;55(6):1686-1688. doi: 10.1161/STROKEAHA.123.044294. Epub 2024 Feb 8. PMID: 38328947.
2. Inoue Y, Shue F, Bu G, Kanekiyo T. Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer's disease. Mol Neurodegener. 2023 Jul 11;18(1):46. doi: 10.1186/s13024-023-00640-5. PMID: 37434208; PMCID: PMC10334598.
3. van den Brink H, Doubal FN, Duering M. Advanced MRI in cerebral small vessel disease. Int J Stroke. 2023 Jan;18(1):28-35. doi: 10.1177/17474930221091879. Epub 2022 Apr 20. PMID: 35311609; PMCID: PMC9806457.
4. Cabrera DeBuc D, Somfai GM, Koller A. Retinal microvascular network alterations: potential biomarkers of cerebrovascular and neural diseases. Am J Physiol Heart Circ Physiol. 2017 Feb 1;312(2):H201-H212. doi: 10.1152/ajpheart.00201.2016. Epub 2016 Dec 6. PMID: 27923786; PMCID: PMC5336575.