Recent advanced brain-imaging studies have shown that the cause of stroke progression is not related to increased blood clot, as was thought, but rather due to the ‘failure’ of bypass channels (collaterals) connecting the blocked artery to its neighbours. However there has been no good explanation of why collaterals fail. Using a stroke model, we made an important discovery which provides the likely explanation. We found that 24 h after small stroke in models, there is a previously unsuspected dramatic, but transient, increase in pressure within the skull (intracranial pressure - ICP). This is predicted to cause collateral failure and our preliminary data suggests it does. Most importantly, we have an extremely promising treatment - 1-2 h of mild body cooling soon after stroke completely prevents the ICP rise. Our aims are 1. to demonstrate that infarct expansion and neurological deterioration are associated with the naturally occurring intracranial pressure rise after stroke and prevented by preventing the ICP rise with cooling treatment; and 2. To demonstrate that collateral failure occurs around 24 hours post stroke and is associated with stroke progression in patients.
In the proposed study we will use our rat stroke model to show that collateral flow drops during the naturally occurring ICP peak 24 h post-stroke and that short-duration cooling prevents the collateral flow reduction and progression of the stroke. These studies will use small-model MRI to enable us to show change in the size of the stroke (infarct) over time in individual models. Our existing data already indicates that use of the affected forepaw deteriorates in models after the ICP rise, mimicking the clinical deterioration in patients and strongly supporting enlargement of the stroke. However to convince the scientific community of the truth of a ground-breaking new idea such as this, we will need clear evidence that the area of brain injury also increases at the same time. In the second part of the study we will capitalise on our world-leading acute stroke imaging database (including clinical outcomes) to gather evidence of the same mechanism occurring in stroke patients. We will use advanced imaging with computed tomography and magnetic resonance perfusion imaging and angiography to show that collateral flow drops before the stroke progression. This proposal will capitalise on our international lead in this rapidly evolving field, provide the necessary information for a clinical trial and also has broader implications for several other important disorders associated with increased ICP and disordered brain blood flow.