Building on Brains for Dementia Research (BDR): A UK Nervous Tissue Network (UKNTN) for the Twenty-first Century

Huge advances have been made in recent years in understanding how our brain and the related nervous system works. Such advances have enabled us to make great progress in learning about the many mental and neurological illnesses that afflict humans so better methods for assessing, diagnosing and treating them can be developed. A lot of this progress has come from studies of animal models of human diseases or from laboratory studies of cells. Such work needs to be confirmed by studies of the human brain and nervous system and this usually requires using donated nervous tissue. In addition, much of this learning has come from direct studies of such human nervous tissue donated by patients and, importantly, by healthy people too. Recent technological advances now enable us to carry out new methods of studying these diseases. However, these technologies require human nervous tissue which is not currently widely available for different reasons, such as the difficulty in obtaining donations from people with mental illnesses, problems with acquiring tissue from outside the brain and the need to obtain more living nervous tissue (derived from tissue donated following surgery on the brain). This proposal responds to the MRC's desire to meet this important need by creating a network of expert centres across the UK who will work together to do this.
We will establish the United Kingdom Nervous Tissue Network (UKNTN) by bringing together five human nervous tissue banks at Newcastle, Bristol, Kings College London, Oxford and Manchester and five expert centres in nervous tissue research at Cambridge (Stem Cells Institute), University College London (Dementia Research Institute), Kings College London (MRC Centre for Neurodevelopmental Disorders), Oxford (Dementias Platform UK) and Exeter (Complex Disease Epigenetics). The five tissue banks already work together as part of the Brains for Dementia Research (BDR) network and already share processes, tissue and data and make this freely available to researchers. We will develop the UKNTN by extending this shared working by adding these five expert centres and by using their expertise to make new types of tissue and data available to researchers. We will do this with eight work packages.
Work package 1 (WP1) will recruit people with mental and neurological illnesses of all ages and ethnicities for nervous tissue donation and use their research data as part of UKNTN. WP2 will obtain samples of blood and the special fluid (cerebral spinal fluid) which protects the brain and link these to clinical and NHS data and later to donated nervous tissue. In WP3 we will report autopsy data on the diseases affecting the donated brains and ask donors for other nervous tissue too. In WP4 we will work with patients and families and researchers to make sure our UKNTN processes work well and meet the needs of everyone. WP5 will build on our experience in the BDR programme to publicise the UKNTN and its work to patients, carers and researchers. WP6 will make freshly donated brain tissue from surgery available for novel studies by researchers across the UK and establish links with UK centres doing this research to share expertise and standardise research protocols. WP7 has four linked main parts. Fibroblast cells will be grown at Newcastle from newly donated tissue, stem cells will be developed from these at Cambridge, mini-brains (cerebral organoids) will be grown from selected stem cells in London and genetic data will be acquired and linked to all this at Exeter. Finally WP8 will bring together all of UKNTN data and link it to anonymised NHS clinical data and make this available to researchers via an established single secure point of access.
After this pilot we will enlarge the network by asking other tissue banks and academic neuroscience centres to join UKNTN and all would work together using the established standards and practices in the UKNTN.

This network will pilot providing deeply phenotyped, multi-modal, integrated tissue and data, including linked in vivo clinical and biosample, autopsy and derived hiPSC, genomic and organoid data, from donors with diverse mental health and neurological diseases (and controls) from across the life course
Work package 1 (participants from mental health and neurology) and WP2 (repeat CSF and blood biosamples) will use well-established methods we have delivered before. In WP3 the neuropathology reporting again follows established methods and will pilot provision of extra-CNS nervous tissue. WP4&5 extend current practices in BDR and existing work on improving tissue access which are not technically difficult
In WP6 fresh human brain tissue from neurosurgery will be transported for immediate slicing for acute electrophysiology (whole cell patch recordings or MEA/calcium imaging). Other slices are preserved using an interface organotypic culture method. AAV transduction will be carried out on day 0. Slices can then be removed from the incubator at intervals for electrophysiology/immunohistochemistry studies, currently up to 28 days in vitro
In WP7 we will generate hiPSCs and brain organoids from a set of well-characterised donors, selecting lines from 4 deeply-phenotyped healthy controls for extensive functional and genomic characterisation at multiple time-points. We will undertake cell-type-specific genomic analyses on matching organoid and post-mortem autopsy samples, enabling a unique comparison of transcriptional and epigenetic signatures. Furthermore, using DNA modification signatures of different neural cell-types we will determine the cellular origin of brain-derived cell-free DNA (cfDNA) using fluid biosamples (WP2) and post-mortem CSF
WP8 (integrated informatics platform providing one-stop-shop for all network data) again extends existing expertise and techniques, including those being established for NHS Electronic Health Records linkage, for UKNTN subjects