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

Lead Research Organisation: University of Cambridge
Department Name: Clinical Neurosciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Nannoni S (2020) Stroke in COVID-19: A systematic review and meta-analysis. in International journal of stroke : official journal of the International Stroke Society

 
Description Cambridge BRAINFest 23-25 June 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We hosted a stall with several exhibits at Cambridge BRAINFest 2017 to advertise stroke research in the department.
Year(s) Of Engagement Activity 2017
URL https://www.neuroscience.cam.ac.uk/brainfest
 
Description Leo and Anne Albert 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk to small conference setting future research direction in Vascular cognitive impairment ; Neuroimaging endpoints in VCID- defining white matter mechanisms and interventions
Year(s) Of Engagement Activity 2018
 
Description Presentation at 2nd CADASIL conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact A second CADASIL conference was organised following the success of the previous years event. Again this study was presented and led to questions and discussion about the specific project and department in general. This also included international speakers to include a Dutch perspective on CADASIL. As CADASIL recruitment was closed no new subjects were recruited at this stage, however there were several requests for information about future studies including the clinical trial that is forming the second part of the study.
Year(s) Of Engagement Activity 2018
URL https://www.neurology.cam.ac.uk/neurology-unit-research-groups/stroke-research-group/events/cadasil-...
 
Description Presentation at BHF Cambridge CRE annual Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact This meeting was organised for all Cambridge scientists involved with the University of Cambridge BHF Centre of Excellence. It is a multi-disciplinary meeting designed to inform and promote collaboration between research groups. The talk led to questions and then further informal discussion about how the techniques could be applied to other conditions.
Year(s) Of Engagement Activity 2018
 
Description Presentation at CADASIL conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact A workshop was organised for those with CADASIL, their families/friends and other interested parties. Various presentations were given, including one on this project, which was followed by questions and later general discussion in formal and informal settings. Many participants were particularly interested in this study and it led to the recruitment of several subjects.
Year(s) Of Engagement Activity 2017
URL http://www.cadasilsupportuk.co.uk/Notes%20from%20CADASIL%20conference%2030%20June%202017.pdf
 
Description Presentation at Cambridge Imaging Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact This meeting was organised for those interested in imaging at Cambridge University. The audience included students and established scientists from across the University and the presentation led to questions and discussion.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Clinical Neurosciences away day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The Clinical Neurosciences department at the University organised an away day to promote interaction and collaboration between members of the department. The talk was well received and led to useful questions. In particular there was discussion about how the methods may be applied in similar conditions.
Year(s) Of Engagement Activity 2018
 
Description Presentation to BHF Volunteers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Third sector organisations
Results and Impact Twenty to thirty local BHF volunteers attended a day where we presented research relating to this grant, amongst other presentations, which led to a discussion or the research and how such projects were run. The volunteers said that they found it very useful to have a better understanding of how the money raised is spent (even though this grant is not BF funded) and were please to see how the projects produce results, which may have real world implications.
Year(s) Of Engagement Activity 2018
 
Description Presentation to BHF head office staff 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact A presentation was given to BHF head office staff to provide them with information about the work we do. It was intended to show the staff how projects similar to those they fund are progressing and the sort of work that the BHF funds. There was a general discussion after the presentations with the staff interested to know about the project in particular and our group in general.
Year(s) Of Engagement Activity 2018
 
Description Presentations at NIHR Stroke Research Workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The National Institute fro Health Research organised a Stroke Research workshop which was attended by a multi-disciplinary range of scientists and clinicians. The presentation was followed by questions and discussion, in particular clinicians were interested to know how the following clinical trial may effect clinical practice.
Year(s) Of Engagement Activity 2018