Aims The aim of this project is to identify a new treatment target for the early stages of dementia with Lewy bodies. Background Dementia affects a person's thinking skills, memory and ability to carry out their day-to-day activities. Around one million people in the UK have dementia. 5-10% of these people have a type of dementia called dementia with Lewy bodies (DLB). In addition to problems with thinking skills, DLB is associated with other symptoms, including visual hallucinations and the symptoms of Parkinson's disease. These symptoms cause significant distress for people with DLB and their loved ones. At present, there is no treatment that can slow the progression of the disease. Microglia are specialised cells in the brain with a range of roles including controlling brain inflammation and removing unwanted material from around brain cells. Previous research has suggested that microglia may play a role in the early stages of DLB. The activity of microglia in the brain can be measured using a specialised brain scan called TSPO PET imaging. This allows us to show whether the number of microglia is increased in early DLB. Toll-like receptors are proteins that sit on the surface of microglia and other cells. They can influence the activity of microglial cells. Microglia and toll-like receptors can be measured in brain tissue from people with DLB after death. The aim of this study is to demonstrate whether toll-like receptors are a good target for drugs aiming to slow the progression of DLB. Objectives 1. Using TSPO PET imaging: quantify microglia in early DLB and assess the degree to which increased microglia are associated with more rapid disease progression 2. Using brain tissue: quantify microglial cells and toll-like receptors in the brains of people with early DLB and examine the association between microglial toll-like receptors and disease processes in DLB Design Objective 1: Brain Imaging We will recruit 50 participants with early DLB, along with 20 healthy people. All participants will have a thorough clinical assessment including measurements of the severity of dementia at baseline, 12 months and 24 months. Blood samples will be taken from all participants at baseline and 24 months, along with an optional lumbar puncture to obtain cerebrospinal fluid (the fluid that surrounds the brain and spinal cord). Participants will have a TSPO PET scan. This will allow us to see if there are more microglial cells in the brains of people with early DLB and if microglial cells are associated with faster progression of dementia. We will repeat the TSPO PET scan after 24 months in participants with DLB. This will allow us to see if microglial cell numbers change over time in DLB. Objective 2: Brain Tissue Analysis We will use brain tissue donated by 30 people who died with early DLB and 30 people who died without any brain disease. Special dyes will be used to look at microglial cells and toll-like receptors under a microscope. Chemicals in the brain tissue will also be measured to understand how toll-like receptors and microglia are associated with other disease processes. This will allow us to understand whether influencing toll-like receptors is likely to slow disease progression in DLB. Patient/service user, carer and public involvement A patient and public involvement (PPI) group was consulted in the development of this proposal in April 2020. A PPI Reference Group will meet throughout the Fellowship and PPI members will be invited to sit on the project steering group. Applications and benefits The findings of this study could rapidly lead to early-stage clinical trials of toll-like receptor-based treatments in early DLB. This study could also lead to the use of TSPO PET imaging to identify appropriate participants and measure treatment response in such trials.

In order to meet the UK's carbon reduction targets, and achieve an energy mix that produces less CO2, we must continue to investigate ways in which to make nuclear power cleaner, cheaper and safer. At the same time, as new reactors such as Hinkley Point C are built, the UK needs to develop the work force who will operate, regulate and solve technical problems in civil nuclear power, in order to capitalise on our investment in nuclear energy. Important in this respect is that the UK currently operates mainly old advanced gas-cooled reactors, fundamentally different from the next fleet of UK nuclear power stations, which will be light-water reactors. Key to this change, in terms of this research project, is that Zirconium is a preferred fuel cladding material in LWRs. A major part of a nuclear reactor is the fuel assembly - the structure that encapsulates the highly radioactive nuclear fuel. Understanding the performance of the materials used to make these assemblies is critical for safe, efficient operation, and they must be able to maintain their structure during normal operation, handling and storage, as well as survive in the unlikely event of an accident, when they become crucial in preventing the escape of radioactive materials. Because of the need to operate nuclear reactors as safely as possible, fuel is often removed well before it is spent, as we currently do not know enough about fuel assembly materials, so must adopt a highly cautious, safety-first approach. This does mean, however, that it is more costly to run a reactor, as assemblies must be replaced well before all the fuel is consumed, and this also means the assembly then - prematurely - becomes additional nuclear waste, which must be safely handed and stored, at further high cost. By gaining greater understanding of how assembly materials perform when irradiated, we will be able to make more accurate safety cases, which will mean that fuel assemblies can be used for longer periods without additional risk. Such knowledge will enable the UK to operate the next generation of reactors far more efficiently, significantly reducing the cost of nuclear power. This is particularly important now, given that the UK is going to have light-water, instead of advanced gas-cooled, reactors, and with it the fuel assembly and its material will change very fundamentally. This research effort will also significantly benefit other countries using nuclear energy, which will establish the UK as a centre of expertise in the area. This will further attract inward investment in research and development in the UK, creating future wealth and employment alongside cleaner energy. A second key theme of the project will be to explore the use of zirconium alloys in critical components for future fusion reactors. The UK has a leading position in defining the materials that will be chosen for the ITER and DEMO international fusion projects, and this theme will contribute to maintaining the UK's reputation as a centre of excellence in fusion research.

The science and engineering of materials have been fundamental to the success of nuclear power to date. They are also the key to the successful deployment and operation of a new generation of nuclear reactor systems. The next-generation nuclear reactors (Gen IV) operating at temperatures of 550C and above have been previously studied to some extent and in many cases experimental or prototype nuclear systems have been operated. For example, the UK was the world-leading nation to operate the Dounreay experimental sodium-cooled fast nuclear reactor (SFR) for ~19 years and a prototype fast reactor for ~20 years. However, even for those SFRs with in total of 400 reactor-years international operating experience, their commercial deployment is still held up. A formidable challenge for the design, licensing and construction of next-generation Gen IV SFRs or the other high-temperature nuclear reactors is the requirement to have a design life of 60 years or more. The key degradation mechanisms for the high-temperature nuclear reactors is the creep-fatigue of steel components. When structural materials are used at high temperature, thermal ageing and inelastic deformation lead to changes in their microstructures. The creep and creep-fatigue performance of structural materials are limited by the degradation of microstructures. The underlying need is to develop improved understanding and predictive models of the evolution of the key microstructural features which control long-term creep performance and creep-fatigue interaction. This Fellowship will use an integrated experimental and modelling approach covering different length and time scales to understand and predict the long-term microstructural degradation and creep-fatigue deformation and damage process. I will then use the new scientific information to make significant technological breakthroughs in predicting long-term creep-fatigue life that include microstructural degradation process. I will thereby realise a radical step beyond the current phenomenological or a functional form of constitutive models which received very limited success when extrapolated to long-term operational conditions. This research will put me and the UK at the forefront of nuclear fission research. This Fellowship will enable the 60 years creep-fatigue life of the next-generation high-temperature nuclear systems by developing a materials science underpinned and engineering based design methodology and implement it into future versions of high-temperature nuclear reactor design codes. In consequence, Gen IV reactor technologies will become commercially viable and Gen IV SFRs will be built globally to provide an excellent solution for recycling today's nuclear waste. This fellowship aims to influence the international organisations responsible for the next-generation nuclear design codes and gaining an early foothold in the international nuclear R&D via this research will give the best chance to secure Intellectual Property and return long term economic gains to our UK.

During this Fellowship, I intend to develop a multi-scale approach that, revealing the structure-relaxation dynamics correlation over a wide time- and length-scale, will direct the design of smart membranes with customised functionalities (while providing a fundamental understanding of commercially available materials). My methodology addressing the microstructure/processing/performance triangle aims to facilitate the transition from theoretical properties to practical applications in materials designed for energy conversion applications and separation science (while it can be extended to biomedical applications). I intend to develop my research at UCL Chemistry, which provides the ideal scientific framework enabling close collaborations with Physical Sciences and Engineering Departments.