Investigating blood-brain barrier integrity in frontotemporal dementia and motor neuron disease

Frontotemporal dementia (FTD) is the 2nd most common form of dementia affecting younger people, with a typical age of onset in the mid-late 50s. Unlike Alzheimer's disease, memory is relatively preserved in FTD patients. However, FTD is a debilitating disease causing severe personality changes, changes in social behaviour, loss of inhibition, irrational behaviours and changes in emotional processing. Around 15% of FTD patients also develop motor neuron disease (MND,

also known as ALS). MND is characterised by selective degeneration of motor neurons, leading to progressive muscle wasting, weakness and paralysis. MND is almost invariably fatal within 2-5-years of symptomatic onset. There are no

effective treatments currently available for either FTD or MND. Our research aims to better understand the molecular and cellular mechanisms underlying disease processes in FTD/MND, and identify potential therapeutic targets for both

diseases. We are particularly interested in how immune and vascular dysfunction contributes to FTD/MND disease pathogenesis.

Neuroinflammation is a common feature of all neurodegenerative diseases, including FTD/MND. Increased microglial activation is observed in affected brain regions, and several pro-inflammatory cytokines are known to be elevated in

patient blood and cerebrospinal fluid. We know from research into other neurodegenerative diseases that excessive inflammation can damage the brain and may contribute to neuronal dysfunction and cognitive impairments. However, this

has been relatively understudied in FTD/MND. We also know that inflammation can reduce integrity of the blood-brain barrier (BBB), which limits its ability to protect the brain. BBB breakdown may also allow infiltration of peripheral immune

cells into the brain, exacerbating neuroinflammation and likely further disrupting neuronal function. Reduced BBB integrity has been reported in other neurodegenerative diseases like Alzheimer's disease, but has not been well studied in FTD/MND.

This project will investigate BBB integrity and neuroinflammation in transgenic mouse models of FTD/MND, using a range of in vivo and ex vivo techniques. This may include (but is not limited to) pre-clinical imaging techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI) and functional ultrasound, behavioural assays to test motor and cognitive function in mice, and a range of molecular/cell biological techniques such as immunohistochemistry, microscopy, ELISA, Western blotting an PCR.

Cell culture techniques will also be used to complement in vivo work and provide mechanistic insights. Finally, key findings may be validated using human brain tissue from FTD/MND patients.