Probing the role of endothelial dysfunction in vascular dementia using advanced imaging

Background

Cerebral small vessel disease (CSVD) is the second leading cause of dementia. Unfortunately, well-established radiological features of vascular dementia, such as microbleeds and white matter hyperintensities, are only observed in the late-stages of disease. There is urgent clinical need for biomarkers that improve earlier diagnosis in order to create a window for therapies and interventions.

A growing body of evidence suggests that dysfunction of endothelial cells (the cells that line the blood vessels) is a critical early event in CSVD. Endothelial dysfunction alters the control of blood flow and this acts as an initiation point for pathology by reducing the ability of blood vessels to dilate and constrict (cerebrovascular reactivity: CVR), which can impaire cerebral blood flow, oxygenation, and neurovascular coupling. All of these processes can be measured using MR techniques and have been identified in human CSVD. However, it is difficult to link this to early stages of the disease, as by the time of diagnosis there is often substantial pathology (inflammation, blood brain barrier breakdown, microbleeds, and progressive white matter and neuronal injury). 

Our hypothesis is that in CSVD, endothelial dysfunction produces early impairments in CVR and neurovascular coupling that are measurable as biomarkers and subsequently drive brain network dysfunction and structural injury. 

To test this temporal association, we will capitalise on two complementary animal models of CSVD available in Edinburgh: an inducible endothelial-specific collagen IV knockout mouse (Kim, et al., 2026. Brain. DOI: 10.1093/brain/awag048) and the phospholipase flippase Atp11b Knock out rat (Quick, et al., 2022. Acta Neuropath. 30: 144(2): 283). Both show alterations in brain endothelial function, with later pathology similar to sporadic human CSVD. Preliminary functional MR data suggests these animals have reduced brain connectivity and this is consistent with our hypothesis. 

We will build on the strengths of the supervisory team with developing and validating clinically relevant MRI biomarkers of cerebrovascular dysfunction including CVR (Stringer, et al., 2025. Ann Neurol. 97(3): 483) and resting state functional MRI (rsfMRI) (Hall, et al., 2022. Stroke. 53(5): 1735). 

Aims

1. Define the temporal evolution of functional cerebrovascular dysfunction in both models using CVR and rsfMRI measures.
2. Validate neuroimaging biomarkers against pathological markers of CSVD to determine whether brain regions with impaired vascular responsiveness are more vulnerable to injury.
3. Use these singly or in combination to propose translational imaging biomarkers to detect CSVD and compare to published human CSVD data where possible.

Techniques

Animal handling and minor surgical procedures (will need Personal License from the Home Office), operation of the MRI scanner, processing of neuroimaging data including computational network analysis, brain tissue processing, immunofluorescence, microscopy and analysis. 

The student will be embedded within a multidisciplinary team and will learn how to present and communicate to a diverse audience, manage multiple tasks, work independently, and critically evaluate information to draw appropriate conclusions.