BRAIN UK BR ain A rchive and I nformation N etwork

1. BRAIN UK BRain Archive and Information Network Collaborator: Prof James Nicoll, University of Southampton

2. Background • Increasing social and economic burden of neurological disease • Increasing frustration at limitations of translational success • Prospective brain banks mainly focus on chronic neurodegenerative diseases - what about stroke, head injury, psychiatric and developmental disorders, rare diseases etc? • Decades worth of archives of characterised tissue in NHS Neuropathology centres • Opportunity to collate and exploit archives for research

3. Neuropathology archives • Neuropathology: 30-40 years as a defined specialty in the United Kingdom. • Based in 29 NHS regional Clinical Neuroscience centres (2-3 million catchment population). • Macroscopic and histological characterisation and diagnosis of post mortem brains. • Residual tissue archived after diagnosis (RCPath guidelines). • Potentially valuable resource for research. • No systematic nationwide organisation or mining of this resource. • Ethical and legal uncertainty: 2000 to Human Tissue Act. • Now pre-HTA archives (“existing holdings”) can be used with anonymisation and ethical committee approval. • Large amount of formalin-fixed paraffin embedded tissue of potential value to increase understanding of neurological disease. • What is available and can this important resource be exploited?

4. Pilot Survey (2007) 5 regional neuropathology services Represents approx 10m population • Duration of collection 28-50 years • Total no. of cases 28,000 • Diagnostic coding system? Yes • Computerized? Yes, since 80s/90s • Paraffin blocks: Huntington’s disease 150 Unexpected infant deaths 35 Stroke (ischaemic) 700 Hereditary spastic paraparesis 13 Head injury 900 Encephalitis (viral) 200 Carbon monoxide poisoning 14 No significant abnormality (i.e. controls) >1,000 • Information available: Neuropathological diagnosis Yes Key patient details (e.g. age, sex) Yes Clinical summary from autopsy report Yes More detailed clinical information No Other data (e.g. imaging, etc.) No Extrapolate UK-wide x5 =approx 150,000 cases

5. Clinical data Immunohistochemistry Morphological studies DNA sequencing PCR Paraffin blocks: room temperature storage, last forever

6. Highly multiplexed single-cell analysis of formalin-fixed paraffin-embedded tissue. Gerdes et al PNAS, 2013 61proteins + DNA FISH in the same section

7. Aim Creation of an electronic linked anonymised database of neuropathology archives to augment existing brain banking facilities

8. Project Outline • “Virtual Brain Bank” – tissue remains where it is under NHS stewardship • Centralised linked-anonymised database including diagnosis, lab number, simple demographic data (e.g. gender and age at death), location and custodian • Centralised application process www.brain-uk.org • BRAIN UK is a “matchmaker” or “broker” • User pays – investigators’ grants fund costs associated with the retrieval, processing and transportation of tissue • MTAs between participating centre and researcher • Acknowledgement of role of local Neuropathologists (e.g. by co-authorship) and participating NHS Trusts is for negotiation on an individual study basis

9. Advantages Well-characterised brain tissue already exists 30-40yrs work - i.e. would take a long time to collect prospectively Some disorders are now rarely encountered because of changes in autopsy practice (e.g. stroke) Paraffin blocks: good for morphology and immunohistochemistry, moderate DNA accessibility Covers neurological disorders comprehensively Large numbers of common disorders Useful numbers of rare disorders Controls Disadvantages No frozen tissue (mRNA, Western blots) Limited clinical details No imaging Not prospective Neuropathology archives vs Brain Banks Conclusion: valuable resource complementary to formal Brain Banks

10. Advantages • A national archive with ‘joint’ ownership by all participating centres • No major capital requirements and relatively low maintenance costs • Not limited to diseases that are able to attract sufficient funding for dedicated brain banks • Participating centres maintain custodianship of their archives

11. Support and Funding • Incorporation of BRAIN UK within the UK Clinical Research Collaboration National Framework Strategy for Brain Banking • Support of the British Neuropathological Society • Initially granted 3 years funding from the Medical Research Council, subsequently extended for 4 years • Additional funding from brainstrust

12. Progress • Developed operational protocols, approached all UK neuropathology centres, obtained local R&D approvals • Collected anonymised autopsy data bases from each participating department and merged them (>60,000 cases) • Obtained REC blanket approval for use of any tissue from participating neuropathology centres for studies that fall under BRAIN UK • Recent extension to include neurosurgical biopsy archive, including muscle and nerve biopsies

13. Participating Centres • Barking, Havering and Redbridge • Barts • Cambridge University Hospitals • Cardiff and Vale University Health • Great Ormond Street Hospital • Hull and East Yorkshire • Imperial College • King's College Hospital • Lancashire Teaching Hospitals • Leeds Teaching Hospitals • NHS Greater Glasgow and Clyde • NHS Lothian • North Bristol NHS Trust • Nottingham University Hospitals • Oxford University Hospitals • Plymouth Hospitals • Royal Free London • Salford Royal • Sheffield Teaching Hospitals • South Tees Hospitals • St George’s Healthcare • The Corsellis Collection • The Walton Centre • University College London Hospital • University Hospital Southampton • University Hospitals Birmingham • Coventry and Warwickshire (*tbc)

14. Preliminary enquiry about tissue availability Application process Application to BRAIN UK including: Name of study sponsor Approval of HOD Details of tissue requirements Study protocol Application circulated to BRAIN UK Committee Feedback to applicant after 2 weeks:approval or comments about protocol Contact details of tissue custodians MTA before transfer of tissue

15. Projects supported • 42 applications supported so far (2011-2015) • Wide variety of conditions including head injury, epilepsy, genetic and developmental disorders • Approval for use of >2000 tissue samples in past 12 months

16. Response of stem cells in the human brain to acute hypoxic/ischaemic injury • ADAM17 in subarachnoid haemorrhage • Protein conformation changes in chronic traumatic encephalopathy and other tauopathies • Are neurodegenerative diseases and gliomas inverse comorbidities? • Investigating inflammation of the normal appearing brain in patients with low-grade glioma • The role of c-Myc in choroid plexus tumours • Characterizing microglia/macrophage polarization in paediatric brain injury • CAA in subarachnoid haemorrhage • A post mortem study of progenitor cells following severe traumatic brain injury • Pilot study: Expression analysis of candidate transcripts potentially involved in human brain tumourigenesis • Large scale genetic and epigenetic screen of chordoma • The role of Numb in the stability and activity of p53 in merlin-deficient tumours schwannoma and meningioma • Designing a glioma panel • Identifying and characterising treatment-resistant subclones in glioblastoma multiforme • The role of Endogenous Retroviral proteins in the development of the tumours of the nervous system and as potential immunotherapy and/or drug targets • Molecular Characterisation of Childhood Craniopharyngioma and Identification and Testing of Novel Drug Targets

17. Strengths/weaknesses • Uses archived tissue that would otherwise be unused • Scale and scope • vs. formal prospective brain banks – complementary, not competitive • Fantastic value for money (one salary 2008 on) • User pays - relies on funding from applicants’ grants • Several letters of support for grant applications provided to date • Paraffin embedded tissue • Relies on goodwill of participating centres • Who invests time in finding suitable cases/blocks for a study? • Managing expectations

18. The future…. • Continue to add post 2006/prospective consented post mortem cases • Biopsy initiative, driven by tumour interest, creating database of over 500,000 cases • Working on unified diagnostic coding system • Promote/advertise (current links with BNS, ABN, BNA, EuroCNS) • Recent CRUK grant application • network of centres currently prospectively banking tumour tissue: Neurosurgeon and Neuropathologist in each of x centres • Ambition to subsequently extend to all willing participating centers in UK • New technology: tissue microarrays, multiplex staining, etc • Supporting tumour research: specific tumour samples, storage of frozen tissue, clinical and imaging data with full consent to research • Centralise data generated • Collaborate with UK biobank (22,000 participants, 976 have CNS tumours) • Physically centralise archives/reports?