Correlating brain and systemic inflammation with peripheral and central neurodegeneration in mice and humans

Post-stroke dementia occurs in around 30% of stroke survivors, impacting significantly on quality of life and also causing a high burden of disease. There are no current effective treatments to prevent or slow the progression of post-stroke dementia and the underlying mechanisms remain unclear.

In experimental models and clinical studies of patients experiencing stroke, immune/inflammatory changes are observed immediately after the event, both in the brain and in the blood. These changes have been proposed as a therapeutic target. There is evidence of long term immune/inflammatory changes post-stroke, which have been suggested as important contributors to the development of post- stroke dementia, and other long-term complications including neurodegeneration in other areas of the body, including the cornea. The cornea is a highly accessible tissue that can be imaged using a non-invasive clinical microscope, which enables direct observation of individual sensory nerve axons, and is used as a surrogate marker of peripheral nerve health. Most experimental models of stroke-induced pathology have focused on the inflammatory response in the brain, which is to be expected given the location of stroke trauma. Few studies have considered how stroke affects the activation of immune cells and inflammatory markers in the systemic circulation (i.e. blood), and other tissues that harbour dense networks of sensory nerves, which belong to the peripheral nervous system. Understanding how stroke can lead to widespread inflammatory changes in the circulation, and how it contributes to peripheral nerve pathology, is important to identify possible targets for therapies aimed at reducing the risk of post-stroke complications.

This project will use an experimental model of stroke to longitudinally measure inflammatory markers and immune cell activation in the brain, blood and eye at acute and long-term timepoints after stroke. The severity of inflammation will be correlated with cognitive function. This project will also include a clinical study of corneal nerve changes and tear neuropeptides (proteins present in tears that indicate nerve health) in stroke patients, to assess whether the cornea can serve as a useful tissue to determine nerve health and immune activation more broadly in post-stroke patients. A wide range of techniques will be used including clinical corneal imaging and tear fluid protein assays in humans, and high-dimensional multi-colour flow cytometry, blood brain barrier integrity and cognitive function testing in experimental models.