The Oxford Control Brain Collection

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

Abstract

The burden of brain diseases is increasing as our society ages. Few of these conditions are currently treatable. Although the last few years have seen a revolution in the genetics and subsequent modelling of diseases in the laboratory, this has not translated into significant progress for patients. It is increasingly recognised that breakthroughs in the field require the direct study of the human brain. In particular, it is important to understand how the expression of new risk genes for neurological disease is regulated in different regions of the normal brain in order to compare it with the disease state. Whilst prospective donation of brain tissue after death is encouraged from donors with specific diseases, this is not the case for donations from healthy individuals. This has resulted in a severe shortage of normal tissue which is essential as a comparator. It is known that when approached sensitively, next of kin are often willing to help with tissue donation following the death of a relative. Here we respond to a call by the MRC to help address the shortage of normal brain tissue donations after death. Oxford is well placed for this as we are experienced in brain banking and have a team of physicians and tissue liaison staff that work closely together. We are already involved in research that aims to improve the Coronial autopsy system and the donation of tissue for transplantation. We are also hosting the new Autism Brain Bank to support research into the biology of a common disease where hardly any tissue is currently available. People who participate in these studies will be asked to consider brain tissue donation for research. Here we ask for support to integrate the patient services for bereavement and transplant coordination to increase the donation of control brains. We anticipate that this approach will result in up to 50 new brain donations per year. With an additional laboratory assistant we will be in a position to ensure high quality tissue preservation and characterisation through our existing infrastructure and support by the Oxford Biomedical Research Centre. Any tissue collected through this approach will be made freely available for researchers via the new MRC UK Brain Banking network which operates at the highest ethical and scientific standards.

Technical Summary

A MRC UK review of brain banking has identified a severe shortage of well characterised normal brains suitable for next generation molecular neuroscience research. A need to provide researchers with tissue from disorders that are common but rarely undergo autopsy such as autism has also been highlighted. Here we propose that the Thomas Willis Oxford Brain Collection (TWOBC) is well positioned to provide a solution to this problem. The TWOBC is part of the emerging MRC UK Brain Banking network, founding member of the Brains for Dementia (BDR) consortium, part of the MRC Cognitive Function and Aging Study (CFAS) and host of the newly formed Brain Bank for Autism. As part of the BDR study we recruit healthy elderly individuals which are cognitively assessed and have pledged their brains for research. However, these numbers are low. Here we propose to retrieve control brain and cord donations matched with blood and relevant peripheral tissues via our Coronial service and in collaboration with our heart valve tissue transplant team. The potential donor cohort in Oxford includes over 800 Coronial autopsies. We have piloted a combined post mortem CT/MRI study on 110 Coronial autopsies with minimal post-mortem delay, 90% of which would be suitable for brain donation based on normal brain CT. We have also identified over 150 potential brain donors per year via our heart valve tissue bank. We have recently received support from the NIHR Oxford Biomedical Research Centre to establish routine DNA/mRNA/protein extraction and quality control protocols in neuropathology. We are actively collaborating with local basic scientists to establish sampling protocols for the application of next generation sequencing techniques to brain tissue. Infrastructure consists of newly built state-of-the art laboratories and tissue storage facilities with space for expansion. This is a single-site application based around a team of neuropathologists, general pathologists, and the directors of the Oxford heart valve bank and patient services (including bereavement). With the requested support we will fuse the heart valve and bereavement team services. Based on the above numbers we estimate that we will be able to collect 30 to 50 well-characterised control brains per annum and make them available for researchers. Some of these brains will have the added value of corresponding high-resolution post-mortem CT or MRI data which we would make freely available for researchers. We are fully HTA and CPA accredited and governance structures, consent and ethics protocols are established.

Publications

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Alexopoulou Z (2016) Deubiquitinase Usp8 regulates a-synuclein clearance and modifies its toxicity in Lewy body disease. in Proceedings of the National Academy of Sciences of the United States of America

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Bereczki E (2016) Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Bridges LR (2014) Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. in Journal of neuropathology and experimental neurology

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DeLuca GC (2015) Olfactory Pathology in Central Nervous System Demyelinating Diseases. in Brain pathology (Zurich, Switzerland)

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Fairfoul G (2016) Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. in Annals of clinical and translational neurology

 
Description Tissue Donation in the OUH Hospitals
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Staff training and patient information concerning tissue donation after death has been rolled out across the OUH Hospitals as a result of our project.
 
Description Brains for Dementia Research
Amount £498,000 (GBP)
Organisation Alzheimer’s Brain Bank UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 04/2018
 
Description MRC Project Grant
Amount £742,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 10/2016
 
Title Brain and spinal cord Tissue for Research 
Description The principle aim of this research project (G1000691) is to provide national and international researchers with high-quality biological samples with associated clinical and quality data. 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact Tissue is being used in a range of projects by academic and industry partners. Output data (samples etc) are available through a regulated requesting system. 
 
Title Liquid nitrogen vapour freezing 
Description Protocol for systematic, rapid freezing of anatomically preserved slices of human brain tissue using a liquid nitrogen vapour storage/transportation dewar. 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact Pilot analysis suggests greater preservation of microscopic anatomy and no ice crystal artefacts. Accurate dissection of frozen region of interest facilitated by preserved anatomy of coronal slices. Freezing method adopted or about to be adopted by other centres (Edinburgh, Autism BrainNet nodes) 
 
Title Thomas Willis Brain Collection database 
Description This is a database of all brain, spinal cord and peripheral organ tissue available for research within the Oxford Brain Bank's Thomas Willis Brain Collection. The archive contains over 6,000 cases from the 1960s to present. The data is available to researchers through Brain UK. 
Type Of Material Database/Collection of data 
Year Produced 2011 
Provided To Others? Yes  
Impact We regularly receive requests from researchers for tissue of patients with rare conditions 
 
Description MRC Brain Bank Network 
Organisation University of Edinburgh
Department Neuropathology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution This grant (G1000691) is for the establishment of a new brain bank for neuroscience research. Part of our work is an active contribution to the emerging MRC brain bank network. This includes contributions to network-wide developments for protocol refinement, consensus sampling protocols and diagnostic criteria. We are also actively contributing to an online tissue repository accessible by any intererested neuroscience researcher.
Collaborator Contribution The network partners contribute IT and management expertise to our project. Partners also contribute research protocols.
Impact Freely available online tissue repository via an MRC network database.
Start Year 2011
 
Description National Health Service 
Organisation Oxford University Hospitals NHS Foundation Trust
Department Department of Neuropathology and Ocular Pathology
Country United Kingdom 
Sector Hospitals 
PI Contribution storage and research use of donated biological samples
Collaborator Contribution diagnostic services and shared facilities / equipment.
Impact Integrated Neuropathology resource bringing together accurate neuropathological diagnostic, material resources and dissemination of research samples.
Start Year 2011
 
Description Alzheimer Research UK Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact A full day with ~150 attendees about clinical and 'translational' brain research with a focus on dementia. Presentation and discussion on the importance of brain banking to understand pathogenesis and outcomes of treatments etc.

Interest by the public to explore tissue donation - reflected in pick-up of leaflets and discussions.
Year(s) Of Engagement Activity 2013
 
Description British Association for Tissue Banking 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Presentation of rationale, ethical framework and strategy for brain banking to the national annual meeting of the BATB.

Better integration of tissue donation for transplant and research. Understanding that these two activities can be linked.
Year(s) Of Engagement Activity 2012
 
Description MRC Bbank Network Donation Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Very useful workshop concerning potential, risks, experiences and ethical considerations about UK brain banking. Discussion with funders, users and scientists.

Development of a coherent strategy for UK brain tissue banking for neuroscience research.
Year(s) Of Engagement Activity 2013
 
Description NIHR BRC Oxford Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation to the public of the link between researching and understanding common brain diseases and human brain tissue donation.

Increase in enquiries about brain tissue donation by memebers of the public.
Year(s) Of Engagement Activity 2012
 
Description Oxford Coroner and Coroner's Officers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The purpose of this grant (G1000691) is to engage a range of professionals with the concept of brain donation for research. Coroner's play a key role in this. The meeting established good working relationships with the Coroner and educated relevant staff about our research project and how they could contribute to its success.

Improved working relationship. Active engagement of key staff relevant for the success of the project.
Year(s) Of Engagement Activity 2012
 
Description Palliative Care Physician Workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Education of palliative care physicians in neurological disorders about the ethical framework, practicalities and scientific impact of brain tissue donation after death.

Increased awareness and confidence of palliative care physicians concerning handling of requests for tissue donations by patients and relatives.
Year(s) Of Engagement Activity 2011
 
Description Parkinson's Disease Local Branch Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Education of patients and relatives as well as health care professionals about the impact brain tissue research has made on our understanding of the pathobiology of Parkinson's disease and other degenerative conditions.

Raised public awareness of our project.
Year(s) Of Engagement Activity 2011