"Crohn's Disease and Ulcerative Colitis are the main forms of IBD. They cause debilitating symptoms affecting 0.78% of the UK population (500,0001 people), and costing UK health budgets approximately £1.5 Billion2 each year. Treatment is with steroids, immunosuppressants and antibody therapies, but results are variable. Over 70% of patients with Crohn’s and 15% with colitis require major surgery3. There is an urgent need to better understand why patients respond differently to treatments in order to improve outcomes and reduce costs. Recent advances in clinical imaging, pathology, and genomic technologies have produced remarkable progress in understanding IBD. However, the power of these technologies cannot be clinically realised until these data can be combined and used in a meaningful way. Our DIH will integrate data from multiple sources and create a secure research resource that allows approved researchers to access data, whilst protecting the privacy of individuals. Patient and public involvement is key to our success. 25,000 IBD patients have already provided consent for their health records to be retrieved and used for medical research. Working together, we will transform our understanding of IBD, drive improvements in diagnosis and treatment, and deliver a data framework to reproduce in other disease areas."

One in 17 people have a rare disease. Rare diseases can be extremely difficult to diagnose, but they often have an unidentified genetic cause. Recent advances in clinical imaging, pathology, and genomic technologies have led to remarkable progress in understanding disease - particularly rare diseases. However, the power of these technologies cannot be fully realised until the immense volume of data generated can be integrated with NHS data, then analysed by researchers in a secure environment that protects the privacy of individuals. Working across the NHS, academia and industry we will use existing tools to transfer data from NHS Trusts to a secure environment that interfaces with the NHS network and shares data with Public Health England. NHS information will then be combined with research data in a cloud-based platform. Initially, we will involve patients with rare diseases recruited to the NIHR BioResource; a national resource of volunteers who have already provided consent that information retrieved from their health records can be used for medical research. This will create a rich research resource with the potential to transform our understanding of rare genetic disorders, drive improvements in diagnosis and management, and provide proof of principle for use in other diseases.

Progressive Supranuclear Palsy (PSP) is as complex as it is devastating for patients and families, combining a kind of movement disorder that does not respond to standard therapies, choking, loss of speech, personality changes, and dementia. Research by our team has shown that in the UK around 7,000 people are living with PSP. Although physically very disabling, it is cognitive and personality changes in PSP that have the greatest impact on quality of life. Despite being slow and unresponsive for many activities, the same patients are often reckless and impulsive for actions that they do make. For example, a person living with PSP may "rush into things" and or "jump to conclusions" without thought for the consequences, or behave in a way that has high risks of falls or choking. These problems are also called "impulsivity". Impulsivity is highly dangerous for patients with PSP, in several different ways. It can make patients walking or moving around alone even though they have a very poor balance and fall. Eating too fast while choking is another form of impulsive behaviour which can lead to life-threatening chest infections. Impulsivity can also be highly distressing for carers and families. There is currently no cure for PSP, although some of the symptoms, including impulsivity, are potentially treatable. However, there is yet a big gap between our knowledge of what is happening in brain cells of patients with PSP and how we should use the available treatments to help people with PSP to achieve the best possible quality of life. We must therefore build better "bridges" between basic studies and clinical trials. To do this, our team will run a series of studies using the most advanced technologies in basic and clinical neuroscience, using advances in imaging, pharmacology, and psychology. We will take advantage of the link between a brain chemical, noradrenaline, and the control of behavior. Noradrenaline is made by a tiny region of the brain called the locus coeruleus. It acts on other parts of the brain, especially the frontal lobe, to help control behavior, including flexible thinking and action control. First, we will quantify the changes in the locus coeruleus, in PSP patients who we have followed through their illness in clinic and who then donated their brain to the Cambridge Brain Bank. Second, we will measure the locus coeruleus in living patients with PSP. The locus coeruleus is small, and hard to see with normal brain scans. Working with Prof Emrah Duzel from Magdeburg, we will use the new technology of ultra-high field magnetic resonance imaging (known as "7 Tesla") to measure the size and degeneration of the locus coeruleus. His groups have developed new robust tools to measure this brain region. We will then use functional magnetic resonance imaging to measure how well the locus coeruleus connects to the frontal lobe and other brain regions. Finally, we will measure the effects of a specific drug that enhances noradrenaline (called "atomoxetine") on impulsvity and cognition in PSP. This drug has been shown by our group and collaborators to improve impulsivity in a significant proportion of patients with Parkinson's disease, and in animal models of impulsivity. It is well tolerated, and approved for such research use in PSP. We believe that the results of our study will lead on to clinical trials for impulsivity in PSP and will eventually contribute to enhance the quality of life of people suffering from PSP.

This proposal will provide funding for a trainee doctor to spend 9 months working on clinical trials in the biopharmaceutical industry. Trainee doctors in the NHS are required to undertake specialist training as set out in a training curriculum. However, a number of training activities related to clinical trials are not easily accessible within an NHS setting. The biopharmaceutical industry has a wealth of experience of designing and running early phase clinical trials, so this is an ideal setting in which to undertake training. The pharmaceutical company AstraZeneca (AZ) has offered to host a trainee doctor for a 9 month placement. This would involve working with a clinical project team to gain experience in a range of activities involved in the design, set up and running of an early phase clinical trial. The trial in question would look at the safety and effectiveness of drugs to treat increased blood pressure in the blood vessels that lead to the liver. This is often caused by liver cirrhosis. There have been no new treatments in this disease area for over 20 years and complication rates are high even with existing treatments, so this is an important trial. In addition to providing clinical trial experience, this placement will also provide wider access to the whole development pathway for new medicines. There will also be opportunities to interact with other early career researchers through a wide range of scientific meetings and events, plus leadership and management training. In this way, the placement creates a unique opportunity for growth of the trainee's skills, knowledge and professional network which will enhance downstream career choices. In return, the trainee doctor would bring to industry specialist expertise and clinical insight gained through working within the NHS at Addenbrooke's Hospital. This will be extremely useful when designing and running the proposed clinical trial for cardiovascular and liver disease. With their close geographical location, this placement will create a unique opportunity for AZ, the University and the NHS to work together in Cambridge to develop professional skills and talent. By encouraging transfer of staff and sharing of knowledge between different sectors, it will, in turn, promote career development for the trainee doctor. Collectively, these factors align closely with the aims of the UKRI Innovation Scholars programme bringing a range of benefits to the wider biomedical sciences sector.

The social context of the research is the rapidly ageing population, and the fact that the number of people in the UK and the world experiencing dementia is increasing. It is predicted that 66 million individuals worldwide will have dementia in 2030. It was in recognition of this grim situation that the Prime Minister launched the Dementia Challenge in 2012. The scientific context is that vast resources have been and are being expended on Alzheimer's disease by governments and the pharmaceutical industry. Almost all of these are based on the amyloid-cascade hypothesis. But this approach has not been notably successful to date, and is looking increasingly doubtful. There are now powerful arguments in favour of looking at alternatives and anticipating a paradigm shift in the understanding of Altzheimer's disease and, probably, of many or most other dementias. There are many indicators suggesting that dementia is often connected with nutritional failures at the neuronal level and that these may be reversed, or at least ameliorated, by changes in lifestyle and diet. It will be enormously advantageous if a simple means can be devised to monitor the severity of dementia, and to identify the at-risk population for whom early remedial action is likely to be helpful. We therefore propose to develop a method of quantifying the degree of dementia, based on physics. It will apply new, sophisticated, analysis methods to brain signals measured from patients, including both electrical (EEG) signals and cardiovascular (blood flow/oxygenation) signals. The intention is to create a device that will be able to provide quantitative measurements of disease progression - or regression in cases where treatment and/or changes in diet or lifestyle are yielding beneficial results. The device we propose is a system consisting of commercially-available state-of-the-art instruments plus novel data analysis algorithms. Its unique features are that it involves 1. Evaluation of both the cardiovascular and neuronal/cognitive oscillations simultaneously and noninvasively, leading to an assessment of the dysfunction in their mutual interactions. 2. Eventually, a standardised presentation of the results in terms of images and a single coefficient spanning from 0 to 100. 3. A relatively comfortable and inexpensive assessment method (especially when compared to MRI-related methods) that can easily be repeated either in the same day or as frequently as is needed or desired. We will test the feasibility of the device, and develop the necessary data analysis algorithms, with the help of 10 clinically assessed dementia patients and 10 healthy controls, in Addenbrooke's Hospital (Cambridge). The data analysis will all be carried out in Lancaster using a range sophisticated methods, some of which are completely novel and highly promising. Assuming that the enterprise is successful, it may be expected to lead in turn to clinical trials, including longitudinal studies, but these are beyond the scope of the present proposal. Nonetheless we can expect to achieve proof-of-concept for the device, operating in a clinical environment. In the longer term, we anticipate that the cost of the device can be substantially reduced, partly by making the near-infra-red-spectrometer (NIRS) purpose-designed, rather than relying on a flexible multi-purpose instrument, and partly by mass-production.