Understanding novel disease processes underlying cerebral small vessel disease and determining whether they can be therapeutically modified

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Disease of the small blood vessels within the brain (cerebral small vessel disease - or SVD) causes about a quarter of all strokes and is the main cause of vascular dementia. Its impact in causing dementia is even greater because many case of dementia particularly in the elderly are caused by a combination of stroke-like disease (primarily SVD) with diseases such as Alzheimer's. Therefore it presents a major public health problem which will only increase as the population ages. Despite its importance there are few treatments for SVD. A major problem in developing new treatments is that we don't fully understand what causes the disease and what makes it progress. Recent data has suggested two new processes may be important. One of these is leakiness of the blood brain barrier (BBB) which separates the blood vessels from the brain tissue. The second is inflammation within the brain. It is now possible to image both of these processes in patients with SVD and this is allowing us, for the first time, to determine how important these processes are in the disease. In pilot studies we have shown we can detect abnormalities in patients with SVD using these brain imaging techniques. We will now apply these techniques in more detail in this project. We will use an MRI technique in which one gives injection of a contrast agent (gadolinium) to look at leakiness of the BBB in patients with SVD. We will determine how common this leakiness is and whether patients with more leakiness have disease which progresses faster. Secondly we will use another imaging technique called positron emission tomography (PET) to image inflammation within the brain. We will determine whether BBB leakiness relates to inflammation and whether both these processes are associated with more rapid disease progression. In the final part of the project we will determine whether we can "switch off" BBB leakiness and inflammation by giving a drug called minocycline. This drug is widely used for other purposes and has been shown to switch off these both BBB leakiness and inflammation in an animal model of SVD. If we can show that these processes are important in SVD in man, and can be switched off by drugs, this will open up a completely new avenue in treatment of this important disease in man.