Development of multiplex RT-QuIC assay for the early detection of dementia and movement disorders: step towards personalized medicine

Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Parkinson disease (PD) are the most common neurodegenerative diseases that create an enormous public health burden with a rapidly aging population. There is currently no definitive test that allows doctors to determine if someone has or will get one of these disorders. At present, the diagnosis is purely based on the symptoms, but by the time this is made the disease process is already too advanced for any therapies to have full impact. There is a clear and urgent need for reliable diagnostic tests that can identify early signs of dementia and movement disorders, and methods that can distinguish between the different types of neurodegeneration e.g. AD / DLB / PD so that drug treatment can be prescribed in a patient specific manner. Early, sensitive and reliable diagnostics will inevitably open an invaluable window for not only to early treatment but also towards finding a cure.

The intention of this DPhil project is to develop such a diagnostic method where samples taken from patients can be  interrogated using a highly sensitive and specific clinic-ready technique/ “kit” called Real-Time Quaking-Induced Conversion (RT-QuIC). An RT-QuIC method, which detects multiple sticky proteins in cerebrospinal fluid (CSF) as a surrogate marker of brain pathology has already been established by the Parkkinen lab to identify signs of early onset Parkinson’s disease (http://www.bbc.co.uk/news/health-37196619). Our aim here is to develop complementary RT-QuIC methods for AD and DLB patients. We anticipate that this will serve as a powerful predictive tool for patients at high risk of developing dementia i.e. patients with mild cognitive impairment, and enable a personalised test that can identify specific variants of the disease. In addition, we are using the RT-QuIC method to understand the disease pathogenesis, particularly the role of different conformational variants, or “strains” of proteins that may contribute to the tremendous heterogeneity of neurodegenerative diseases by showing different morphology, seeding and/or cross-seeding propensities, strain-specific neuropathology and different levels of neurotoxicity.

The proposed project will require vast biochemical, biophysical, molecular neuroscience and pathological skills and knowledge provided by the unique translational training environment formed by Dr. Parkkinen and her local and international collaborators who are all experts on the field. Dr. Parkkinen’s Molecular Neuropathology research group is based at state-of-the-art facilities at the Academic Unit of Neuropathology (AUN) and Oxford Brain Bank which are part of the Nuffield Department of Clinical Neurosciences (NDCN) in the University of Oxford. Research into neurodegenerative diseases has a high priority and profile within the University of Oxford and especially NDCN. Dr. Parkkinen is also an integral part of the Oxford Parkinson’s Disease Centre (https://www.dpag.ox.ac.uk/opdc) which is a multidisciplinary group of internationally recognised scientists with strengths in genomics, imaging, neuropathology, biomarkers and cell and animal models. Regular meetings are arranged for all post-graduate students within AUN/NDCN, and feedback and guidance is provided to ensure completion of the degree within the allocated time. All the necessary funding is provided by Dr. Parkkinen’s successful Weston Brain Institute and Parkinson’ UK grants.