Translational Neuroscience & Dementia Research
Pan-European grants involving over 50 partners
ARUK Drug Discovery Institute Award
MRC Centre of Excellence Award
Wellcome Trust Strategic Award (Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease)
We have three main areas of activity, all aiming towards secondary prevention of dementia. By understanding disease mechanisms we seek potential therapeutics; through discovery of biomarkers we hope to enable preventative trials, and with informatics we utilise large biological and clinical datasets in the support of translational neuroscience.
From mechanisms to drug development
Alzheimer’s disease has two main pathological lesions – the plaque and the tangle – although many other pathological processes are involved in the brain, including inflammation and vascular damage. Some twenty years ago I worked in the group of Brian Anderton at KCL to try and find the enzymes responsible for phoshorylating tau protein, a process thought to underlie the formation of tangles. This work led me, and others, to Glycogen Synthase Kinase-3 (GSK-3) and from there to the regulation of this kinase by insulin and the wnt signalling pathways. My group has over the years demonstrated that GSK-3 is one of the predominant tau-kinases and that inhibition of GSK-3 prevents tau phosphorylation in model systems and that inhibition of GSK-3 activity is necessary for long term potentiation, a mechanism of brain plasticity that perhaps is at least in part responsible for some of the cellular processes necessary in forming memories. We have led trials of GSK-3 inhibitors as potential disease modification agents and are now further refining our understanding of the disease process and developing alternative targets for drug development for disease modification.
Blood based biomarkers to enable clinical trials
Alzheimer’s disease has a long prodromal period – a time when the pathological process is active in the brain but not yet causing substantial, if any, symptoms. If we could identify people in this pre-clinical phase then there might be a ‘window or opportunity’ whereby drugs would be more likely to be effective than later when the disease was more fully established and neurons were being lost. In this window of opportunity a disease modification that was effective would be in effect a preventative therapy. However, in order to identify people in this phase of disease for clinical trials and one day for intervention, then biomarkers are needed. We have chosen to focus our attention on searching for blood based biomarkers to complement the work of many other groups that has been so successful in identifying spinal fluid markers and using imaging, including PET imaging, as markers of disease. A blood based marker would be less invasive and more readily available than CSF or PET imaging. Using a range of approaches we and our collaborators have looked for such a biomarker in the proteome, the transcriptome, the epigenome and the metabolome. We have used a range of approaches in all of these studies in discovery and then replication and validation phase. Perhaps the most important contribution we have made is not just in the actual findings, many of which have been replicated by others, but also in the design of studies as we have moved away from a case-control and more towards an ‘endophenotype’ approach whereby we search for a biomarker in comparison to a continuous and quantitative indication of disease status. Using these technologies and this design we have got close to a set of markers to be used as a biomarker, most likely in combination with other specific markers of pathology.
The power of numbers – informatics in translational research
In both our mechanisms and biomarkers work we are analysing relatively large datasets using a range of statistical approaches including machine learning. As a consequence of this informaticians and statisticians have come to play an increasingly important role in the group. Building on this expertise, we are now turning attention to datasets beyond genomic and proteomic to clinical and imaging data. Through initiatives such as the UK-Clinical Records Interactive Search (UK-CRIS) process - generated first at the Maudsley Hospital in south-east London and now rolling out across the UK, to the European Medical Information Framework - a collaborative initiative to speeding up the development of, and patient access to, innovative medicines, our group has access to very large datasets from cohort and other research studies and from routine care and are using these data to advance experimental medicine seeking preventative strategies for dementia.
Over the next year our group will seek to accelerate work towards disease modification of dementia including:
- The Deep and Frequent Phenotyping study; a very detailed multimodal biomarker study to identify markers of progression in preclinical dementia
- Further drug development programmes building on successful compound identification in primary and secondary screens
- Validation and then qualification of blood based biomarkers of dementia and preclinical disease
- Identification and replication of blood based biomarkers for Parkinson’s disease
- Working to establish the Dementias Platform UK, especially the informatics components, establishing the European Prevention of Alzheimer’s Disease public private consortium and building on the European Medical Information Framework a data aggregation and access programme
- Using medical informatics from electronic medical records to understand the role of inflammation in dementia aetiology