Maximising a small vessel disease brain bank resource

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Clinical Brain Sciences

Abstract

The blood supply for the interior of the brain comes from large blood vessels which divide and get smaller, and enter the brain tissue. They continue to branch becoming small arterioles and finally capillaries, at which point nutrients from the blood pass in to the brain tissue. The capillaries then begin to join up again to form venules taking blood away from the brain. These arterioles, capillaries and venules can be affected by a disease process called small vessel disease (SVD) which damages the deeper parts of the brain. This white matter damage can be seen on brain scans, particularly magnetic resonance imaging (MRI), as a range of different lesions including white matter lesions (WML), enlarged perivascular spaces, microbleeds and microinfarcts. These lesions are very common, being seen in almost half of all people with dementia, including Alzheimer's disease and vascular dementia. However, the picture is complicated as these changes are also seen in other conditions including different kinds of stroke, including brain haemorrhages, and depression, and are also seen with ageing without obvious cognitive problems.
To adequately study why and how SVD damages the human brain, a process known as pathophysiology, we need to look at human brain tissues affected by SVD at different stages of brain injury. Animal models are of limited use, as animals do not get SVD and the models being used are genetically modified to have some aspects of the human disease, but do not encompass the whole picture. Our proposal will develop a human brain bank to support biomedical research into the pathophysiology of human SVD locally, nationally and internationally. To adequately do this we do not just need access to brain tissue after death. We need to have access to the lifelong medical records of individuals donating their brains such that we can assess what risk factors they have been exposed to (such as high blood pressure, diabetes, obesity and smoking history), and we need to link this to investigations that have been undertaken during life, such as brain scans (MRI) and blood tests such as cholesterol. As access to patient data is very tightly controlled, this data needs to be stored in a secured site (a data safe haven) and accessed only by authorised individuals. Researchers can be provided with tissues with associated clinical data (age, sex, BMI, smoking history, blood pressure etc) but in a confidential way- the researcher cannot work out the identity of the donor from the information provided.
To date we have several clinical cohorts who have donated brains post mortem, an we are looking to develop a similar brain donation programme around patients who have very small strokes caused by SVD. We will then be able to offer biomedical research groups access to all aspects of human SVD, covering deep small strokes, brain haemorrhages, SVD with cognitive problems, and SVD with no cognitive problems.

Technical Summary

We will develop a deeply annotated tissue resource for biomedical researchers studying the pathophysiology of SVD. We will integrate a number of established clinical cohorts within the Edinburgh Brain Bank, and data detailed data linkage such that we can access primary and secondary clinical data from all patients who donate brain post mortem, and further link these with additional tests such as imaging.
While there are some animal models that replicate to a degree some elements of human SVD, to truly investigate the pathophysiology of this complex and poorly understood condition, human brain tissue is required. This will allow research groups to interrogate human brain tissues generally (such as array technologies) or locally (such as laser capture microdissection) to better understand cellular events and changes, which in turn could lead to more targeted and relevant animal models. Assessment of cellular pathophysiology is enriched by direct correlation with clinical phenotype, and this is now seen as a key element of any successful human biobank- researchers need more than pathologically annotated human tissues, they need the deeper annotation delivered by linked clinical and pathological data.

Planned Impact

The proposed facility will link a number of existing clinical cohorts in to a unified donated brain bank resource with detailed clinical information and significant linked imaging and cognitive data. The clinical cohorts cover the range of pathologies seen in small vessel disease (SVD) including lacunar stroke, intracerebral haemorrhage, and pathological correlates of cognitive decline.
Considerable advances in our understanding of SVD have ben made by studying well defined clinical cohorts with in vivo imaging. However, there are many research groups across the UK and international who are studying the pathophysiology of SVD at a cellular level but, to date, have been limited to animal models which often poorly replicate the human disease, or human brain tissue in which SVD is an incidental finding, such as Alzheimer's disease brains with associated SVD. The proposed facility will offer a disease-focused, highly characterised human brain resource to facilitate detailed cellular level interrogation of pathophysiology.

Ultimately through an understanding of pathophysiology we would hope that new therapeutic targets would be available. We actively seek collaboration with the Pharmaceutical industry, and all our donated cases are fully consented for use by industry.

The development of a SVD brain bank linked to data will provide an excellent training resource for the next generation of academic neuropathologists and neuroradiologists, both areas in which recruitment has been an issue in recent years. We anticipate that the harmonisation of several clinical cohorts with brain banking and data linkage, including both in vivo an post mortem, will show how a successful brain bank resource can support the biomedical research community, and how collaboration between the clinic, radiology and pathology can lead to a highly relevant research facility.

Through the Charity collaboration associated with this application (The Stroke Association) we feel that a valuable impact relates to public engagement, particularly engagement with relatives of those who have died and generously donate their brains, and of patients who have been affected by the clinical consequences of SVD. Through our public engagement programmes they can be re-assured that there is active research in to SVD, an that donated brains are being use responsibly to support research, and that there are active research programmes looking for new targets for therapies.

Publications

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Horsburgh K (2018) Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology. in Clinical science (London, England : 1979)

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Humphreys CA (2019) A protocol for precise comparisons of small vessel disease lesions between ex vivo magnetic resonance imaging and histopathology. in International journal of stroke : official journal of the International Stroke Society

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Keogh MJ (2018) Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains. in Journal of neurology, neurosurgery, and psychiatry

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Owasil R (2020) The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. in International journal of molecular sciences

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Smith C (2018) Brain donation procedures in the Sudden Death Brain Bank in Edinburgh. in Handbook of clinical neurology

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Wardlaw JM (2019) Small vessel disease: mechanisms and clinical implications. in The Lancet. Neurology

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Wei W (2019) Frequency and signature of somatic variants in 1461 human brain exomes. in Genetics in medicine : official journal of the American College of Medical Genetics

 
Title Post Mortem imaging 
Description We have developed a novel approach to imaging of post mortem brain samples allowing us to directly correlate microscopic/molecular changes with neuroradiological poarameters, such as white matter hyperintensities. This allows us to directly study the molecular and cellular changes that underpin radiological changes and assess how they contribute to disease progression. 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? Yes  
Impact We are aware of other international brain banks who are looking to implement our protocol. 
URL http://journals.sagepub.com/doi/abs/10.1177/1747493018799962?url_ver=Z39.88-2003&rfr_id=ori:rid:cros...
 
Description Collaboration with University Laval to develop a collaborative radiologic-pathological approach to small vessel disease 
Organisation University of Laval
Country Canada 
Sector Academic/University 
PI Contribution We have hosted colleagues from University Laval in Edinburgh to study our small vessel disease grading system, to replicate within their cohorts.
Collaborator Contribution We developed the pathology- imaging correlation, and developed the grading system.
Impact Visiting scholar from Canada
Start Year 2019
 
Description National awards ceremony 
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 The Stroke Association Research awards event 2nd May 2018 at Guildhall London, at which the award for the small vessel disease brain bank was presented. The audience comprised patients, carers, academics and media groups.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/clinical-brain-sciences/news/news-jan-jun-2018/stroke-assoc-awardees-2018