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

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.

Cerebral small vessel disease is a major cause of stroke and the major cause of vascular dementia. Despite its importance we have limited understanding of its pathogenesis and this gap in knowledge has hampered development of new therapies. There are few proven treatments for this important condition.

Recently it has been suggested that increased blood brain barrier (BBB) permeability and neuroinflammation may play a role in the disease. In an animal model a pathophysiological cascade has been suggested involving these disease processes, and excitingly a drug which inhibits these processes (minocycline) resulted in reduced white matter damage and improved cognitive function.

In this Challenge grant we will apply state of the art imaging techniques which allow detection of BBB permeability in individual patients (using a contrast based MRI technique) and neuroinflammation (using 11C-PK11195 PET). In the first phase in an observational study we will determine the patterns of BBB permeability and neuroinflammation, whether these two processes overlap, and whether areas of increased permeability and inflammation progress to damaged brain tissue. We will study 20 patients with sporadic SVD. In addition we will study 20 patients with the younger onset genetic form of SVD, CADASIL; this will allow us to study presymptomatic individuals to determine the role of these processes very early in the disease.

In the second half of the study we will perform a randomised controlled trial determining whether minocycline, the drug which has been used successfully in the animal model and which has been demonstrated to have effects on both stabilisation of the BBB and reducing neuroinflammation, results in a reduction in BBB permeability and neuroinflammation as measured by these imaging techniques. For the RCT we will study 44 patients, 22 given minocycline and 22 given placebo, in a double blind design.

Cerebral small vessel disease represents an enormous, and increasing health problem. It is the most common cause of vascular cognitive impairment and dementia, which is the second most common cause of dementia, and causes lesser degrees of cognitive impairment in many more individuals. It is also the major cerebrovascular disease contributing to mixed dementias which account for perhaps the majority of dementias in elderly individuals. With the increase in the ageing population SVD will become an even more significant health problem. SVD has major implications not only for the individual patient, but also for their families and carers, as well as for society in general. Despite its Public Health importance there are few treatments, particularly for established disease. This need has been recognised by many bodies worldwide; for example at a recent workshop hosted by the Stroke Association and bringing together a number of funders the needs for new treatments was highlighted, and a major reason for the lack of effective treatments was incomplete understanding of what causes SVD.

This proposal will bring together novel techniques for imaging blood brain barrier disruption and neuroinflammation and apply them to patients with SVD. If we can show that these processes are important in disease progression, and more importantly can be delayed by drug treatment, this will open up a completely new avenue in treatment of SVD. We will use a widely available drug (minocycline) to investigate this question, but there are many other potential drugs targeting blood brain barrier disruption under development for other clinical indications, particularly acting via inhibiting matrix metalloproteinase disruption, which could be applied to the disease.

Therefore our findings could have important implications:
1) In opening up a novel line of treatment for this very important and common but poorly treated disease.
2) In demonstrating the importance of BBB disruption and neuroinflammation as t disease processes in SVD progression, and opening up the area to pharmaceutical companies for targeting with other drugs stabilising the blood brain barrier and reducing neuroinflammation.