The goal of this project is to determine the biological mechanisms behind water exchange MRI signals used to assess blood-brain barrier (BBB) integrity. The BBB is a vital structure that protects the brain by tightly regulating the exchange of substances between the bloodstream and brain tissue. Dysfunction of this barrier is a key feature in many neurological disorders, including Alzheimer’s disease, stroke, and small vessel disease. Several MRI methods have been developed to non-invasively assess BBB function by measuring how water moves across the barrier: these techniques are beginning to enter clinical trials, especially in diseases like Alzheimer’s or stroke. 

However, we do not yet know what these MRI signals are actually measuring at the biological level. This uncertainty limits their interpretability and clinical value. This project aims to uncover the biological pathways that influence these MRI water exchange signals by targeting two key components of the BBB. The first is aquaporin-4 (Aqp4), a protein channel that facilitates transcellular water transport. The section is claudin-5 (Cldn5), a protein that seals the gaps between the cells in the vessel walls restricting paracellular exchange. 

Emma Thomson will use AAV-based gene silencing to selectively knock down Aqp4 or Cldn5 in one hemisphere of the mouse brain, creating controlled and localised BBB disruptions, and allowing us to observe how each MRI sequence responds to disruption of a specific transport mechanism. She will then use advanced 3D imaging with synchrotron X-ray microCT at the DanMAX facility (MAXIV, Lund) to visualise the correlations between the MRI derived metrics and the distribution of proteins. This combined approach will allow us to link MRI signals to the underlying biology. This will significantly improve the interpretability of MRI, helping researchers and clinicians better detect and understand early signs of neurological disease.