from left to right: horizontal molecular MRI of endothelial activation, blood-brain barrier permeability map, fractional anisotropy map, 3D-tractography top-view, and volumetric 3D-reconstruction (red, corpus callosum; green, internal capsule)
Understanding neurovascular dysfunction in ageing and dementia
The brain depends on a tightly regulated vascular network to maintain a healthy environment and support neuronal function. Central to this is the blood-brain barrier (BBB), a specialised interface formed by endothelial cells and supported by pericytes, astrocytes, and other components of the neurovascular unit. Increasing evidence indicates that alterations in this system contribute to cerebral Small Vessel Disease (cSVD), Alzheimer’s disease (AD), and age-related cognitive decline.
Our research focuses on understanding how pericytes and endothelial cells interact to maintain vascular health, and how disruption of these interactions contributes to BBB dysfunction, impaired cerebral blood flow, vascular inflammation, and white matter injury.
Our previous studies in humans demonstrated that BBB breakdown develops during normal ageing, becomes more pronounced with cognitive impairment, and is associated with pericyte injury. We also established that BBB dysfunction in individuals carrying the APOE ε4 allele, a major genetic risk factor for AD, is associated with and can predict cognitive decline.
Using experimental models, we have shown that pericyte deficiency causes microvascular damage, BBB disruption, white matter injury, and neuronal dysfunction. More recent work has revealed how pericyte loss can compromise cerebral blood flow and neurovascular coupling while triggering inflammatory and phenotypic changes in endothelial cells.
Importantly, our recent investigations of human cSVD have identified pericyte loss and endothelial activation as distinct but potentially interconnected vascular alterations, strengthening the relevance of these mechanisms to human disease.
Building on these discoveries, we seek to understand the molecular and cellular mechanisms underlying neurogliovascular dysfunction and identify vascular-targeted therapeutic strategies to preserve brain health and cognitive function.
Main Objective & Research Goals
Our overarching objective is to understand how ageing and disease alter the interactions between vascular and immune cells in the brain, and how these changes contribute to neurodegeneration and cognitive decline.
We combine experimental models, human brain tissue, advanced neuroimaging, and molecular profiling to investigate five interconnected research areas:
1. Pericyte-endothelial interactions and BBB integrity
Determine how pericyte dysfunction or loss alters endothelial identity, BBB permeability, vascular stability, and the molecular pathways responsible for maintaining a healthy neurogliovascular unit.
2. Endothelial activation and cerebrovascular inflammation
Investigate the mechanisms driving endothelial inflammatory activation, including adhesion molecule expression, vascular immune signalling, and their consequences for BBB function and cerebral perfusion.
3. Cerebral blood flow and neurovascular coupling
Understand how vascular cell dysfunction affects cerebral blood flow regulation, neurovascular coupling, tissue oxygenation, and ultimately neuronal and cognitive function during ageing and disease.
4. Neurovascular-immune interactions and white matter injury
Explore how microglia, peripheral immune cells, and vascular cells interact during cerebrovascular dysfunction, and how these interactions contribute to vascular remodelling, inflammation, and white matter pathology.
5. Translational biomarkers and vascular-targeted therapies
Identify imaging and molecular biomarkers of vascular dysfunction in human disease and evaluate interventions targeting the cerebral vasculature to restore BBB integrity, improve brain perfusion, and protect cognitive function in cSVD and AD.
Main Techniques
Our laboratory combines in vivo neuroimaging, cellular and molecular biology, experimental models, and human neuropathology to investigate the mechanisms of neurovascular dysfunction across multiple scales.
Magnetic Resonance Imaging (MRI)
MRI is central to our research, allowing us to investigate vascular and brain dysfunction longitudinally in living experimental models.
We employ advanced MRI approaches to assess BBB permeability using dynamic contrast-enhanced imaging, cerebral blood flow using arterial spin labelling, endothelial activation using targeted iron oxide particles, and white matter microstructure using diffusion MRI. Together, these techniques provide complementary measures of vascular integrity, perfusion, inflammation, and tissue injury.
MRI-based mouse brain atlas
Positron Emission Tomography (PET)
We use PET imaging, including combined PET-MRI approaches, to investigate molecular processes associated with neuroinflammation and neurodegeneration.
For example, the TSPO radiotracer [¹⁸F]DPA-714 enables us to investigate changes in neuroinflammatory signalling, complementing MRI-based assessments of vascular and tissue dysfunction.
18F-DPA-714 microglial PET-MR in mouse
In Vivo Two-Photon Microscopy
Two-photon microscopy provides high-resolution, real-time imaging of the brain’s microvasculature through cranial windows.
This approach allows us to examine pericyte dynamics, capillary structure, vascular blood flow, BBB permeability, and interactions between vascular cells and microglia. By monitoring these processes over time, we can investigate how vascular dysfunction develops and evolves during ageing and disease.
Live two-photon microscopy showing the mouse brain vasculature (cyan, 70 kDa Dextran) and pericytes (red, endogenous tdTomato)
Human Neuropathology and Advanced Microscopy
We investigate human post-mortem brain tissue to identify vascular alterations associated with cSVD, AD, and related dementias.
Using multiplex immunohistochemistry, confocal microscopy, and quantitative image analysis, we characterise pericyte coverage, endothelial activation, vascular integrity, and the relationships between blood vessels, immune cells, and surrounding brain tissue. These studies help establish the relevance of findings from experimental models to human disease.
Coronal section of a mouse brain showing the ICAM-1 positive vasculature using a spinning disk confocal system
Molecular Profiling and Experimental Models
To uncover the mechanisms underlying neurovascular dysfunction, we integrate cell-specific genetic manipulation, single-cell/nucleus RNA sequencing, spatial and molecular profiling, proteomics, and computational analyses.
These approaches are complemented by experimental models of ageing, AD, and cSVD, as well as behavioural assessments, enabling us to connect molecular and cellular changes with vascular dysfunction and cognitive outcomes.
Ultimately, combining these techniques allows us to move from identifying early vascular alterations to understanding their mechanisms and developing strategies to protect the ageing brain.