Investigating how fluid is drained from the brain in vascular dementia

Research project: Vascular dementia: failure of fluid drainage from cerebral white matter

Lead investigator: Professor Roxana Carare
Institution: University of Southampton
Grant type: Project Grant
Duration: 36 months
Amount: £200,131 (this project is part of a joint funding call with Stroke Association and British Heart Foundation- Alzheimer's Society is funding £74,039 of this)

Why did we fund this project?

Comments from members of our Research Network:

"An important project proposal succinctly summarised, with such potential for future targeted treatments. Extremely relevant."

"Findings may assist long term in development of treatment for vascular dementia."

"An important project that aims to find out more about how the pathways for the elimination of toxic waste from the brain are affected in vascular dementia. It will use post mortem brain tissue and animal models. It could, if successful, lead to targetted treatment for vascular dementia, aimed at improving the drainage of fluid from the brain."

What do we already know?

As well as supplying the brain with blood, the small blood vessels in the brain also carry away toxic waste products. The waste is removed along tiny pathways in the blood vessel walls. The pathways are anchored to the surrounding cells, and if this anchoring is disturbed the pathways can't remove waste properly. 

The walls of blood vessels are also lined with water channels, which allow water to pass between blood vessels and brain tissue. If there aren't enough water channels, water can build up in the walls of the blood vessels and destroy the anchorage around the drainage pathways. This makes small vessel disease (SVD), more likely. Small vessel disease is a known cause of vascular dementia. 

Professor Carare and her team's previous research has shown that risk factors associated with the failure of brain fluid to drain properly include age, possession of the Alzheimer's risk gene APOE4  and a high fat diet in early to mid-life. Changes in the structure and composition of drainage channels are also associated with these factors. 

Most people with vascular dementia have damage to their brain tissue which can be seen on an MRI scan. It is assumed that this damage is due to fluid leaking out of blood vessels and into brain tissue, but the scientific evidence for this is not clear. This project will tell us more about whether the way fluid is drained from the brain is affected in vascular dementia.

What does this project involve?

This research aims to find out how these waste-removal pathways are affected in vascular dementia, by looking at the way the pathways are anchored to the blood vessels and how water channels in the vessel walls are affected.

The researchers will look at the brains of patients who died with vascular dementia to examine the water channels in the blood vessels, and how their waste-removal pathways are anchored. They will compare this to their observations of mouse models that are missing either the pathway anchoring system or water channels.

The researchers will also look at how waste is cleared from the brains of mice that have faulty water channels or disrupted anchoring of waste-removal pathways in the blood vessels in their brains. These mouse models should also be suitable for testing new treatments aimed at restoring the safe removal of fluid and waste to prevent vascular dementia. 

How will this benefit people with dementia?

Because we don't know exactly how vascular dementia is caused, it is hard to find targets for effective treatments. If this research suggests that failure of the brain's waste-drainage system is a key cause of vascular dementia, it could lead to targeted treatments for vascular dementia which improve fluid drainage from the brain. 

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