Analysis and imaging of metal-ion accumulation in neurodegenerative disease

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In many neurodegenerative diseases, brain iron concentrations are abnormally high. For example, in Parkinson's disease (PD), iron levels are doubled in the region containing the neurons responsible for motor control, and typically 80% of the motor control neurons are known to have died prior to the onset of clinical symptoms. Magnetic resonance imaging (MRI) of iron accumulations may provide an ideal method for early diagnosis, but in practice we do not know enough about the state of the iron. This hinders progress in understanding underlying disease mechanisms, in interpreting MRI images, and in determining the effects of chelation treatments to remove excess iron.The role of iron in neurodegeneration is not fully understood, partly because conventional research techniques do not provide enough information about the type of iron accumulations. This is critical, because unless iron is managed properly and stored in a relatively inert form, it can partake in chemical reactions that create a toxic environment for cells. Our proposed research will enable substantial progress in these areas, by directly correlating information from a new synchrotron x-ray approach with MRI.We will study the basal ganglia, which exhibits the most significant iron accumulation, in two relevant and incurable diseases: PD, and Neurodegeneration with Brain Iron Accumulation (NBIA), which is very rare, but shares many features with PD. With our synchrotron x-ray imaging approach, it is possible to look directly at autopsy tissue sections and determine the forms that the iron accumulations take, and their relationships with other metal accumulations and disease pathology. This information will be used to explain features seen in MRI analysis of the same tissue samples, and transferred to MRI analysis of PD and NBIA patients and healthy controls to understand what is present in vivo. We will support this research by quantifying iron compounds in autopsy tissue with magnetometry, and then extracting the iron compounds and examining them with electron microscopy to confirm their properties in detail. Keele University will be the host institution for this research, where there is access to world-class expertise directly relevant to this proposal, and the overseas portion of the Fellowship will be held at University of Florida. The synchrotron x-ray imaging and analysis of autopsy tissue will be performed at the Advanced Photon Source in Chicago, where University of Florida has regular access to facilities purpose-built for the type of research proposed. We will also develop the synchrotron analysis approach at the new UK synchrotron, DIAMOND, ensuring that world-class research in this new and expanding area can in the future be achieved in the UK. The MRI work will involve imaging of autopsy tissue sections, and a clinical study of Parkinson's disease patients, NBIA patients, and healthy age- and sex-matched controls. All this will be performed at the outstanding MRI facilities at the University of Florida McKnight Brain Institute, and for sample characterisation there will be direct access to world-class facilities at the National High Magnetic Field laboratory in Tallahassee, through University of Florida. The magnetometry and electron microscopy work will be performed in the UK, working with existing collaborators at University College London and at Cambridge University. These collaborations ensure access to excellent facilities, as well as providing frequent opportunities for academic discussion with experts in the respective fields.We will use a unique combination of physical sciences techniques to characterise iron accumulations in critical regions of the brain in PD and NBIA. This knowledge will be used to determine the potential of iron accumulations for early diagnosis using MRI, to further our understanding of PD pathogenesis, and to support the development of safe iron chelation therapies.