The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson's Disease Dementia

Parkinson's disease (PD) causes problems with walking and movement, but around half of patients will also develop dementia within the first 10 years of their disease course. The primary goal of this study is to better understand the earliest changes in the brain that lead to memory problems and dementia in PD. These early changes would be the best targets for new treatments to prevent or slow dementia, and may be relevant not just to PD dementia but to other forms of dementia (including Alzheimer's disease), because a number of these conditions share similar features when brains are examined after death. In most conditions involving dementia, it is difficult to study the earliest brain changes before symptoms emerge, but this is possible in PD because the dementia comes later than the movement problems. In addition, my previous work has identified a method of determining whether an individual with early PD is at high risk or low risk of going on to develop a dementia within the next few years (based on performance on thinking tests and genetic variation). This means that we can look specifically at what brain changes are occurring in high dementia risk patients before the dementia actually becomes apparent. My previous research has contributed to the theory that 2 processes - build-up of a protein called tau, and inflammation within the brain - might be particularly important in the development of PD dementia. The main aim of this study is to investigate this theory by comparing markers of these processes in 2 groups of patients: a group at high dementia risk, and a group at low dementia risk (20 per group). Healthy volunteers of similar age will also be included for comparison. Inflammation and tau deposits will be measured using a special type of brain scanning (PET imaging), as well as in the fluid that bathes the brain and spinal cord (cerebrospinal fluid), and in the blood. Participants will undergo PET scanning at the beginning of the study, as well as a lumbar puncture to collect a cerebrospinal fluid sample, a blood test, and clinical and memory assessments. They will be seen again at 18 months to assess changes in their clinical condition and memory, and have a blood test. Scans, lumbar punctures and blood tests will then be repeated at 3 years to look at how measures of inflammation and build-up of tau protein have changed, and how they relate to the development of memory problems and dementia. As well as measuring markers of inflammation and tau on the scans and in the fluid samples, immune cells will be extracted from blood and used in experiments in the laboratory to look at how they respond to tau and other key proteins. Finally, the most promising of the inflammation and tau-related markers identified in cerebrospinal fluid and blood will be measured in a separate large group of approximately 200 patients and 100 healthy individuals to confirm their value in tracking progression to dementia. The research will specifically address these key questions: 1. Are inflammation and tau deposition important early events in the brain as Parkinson's dementia is developing? 2. Can we measure small clumps ('oligomers') of tau and other related proteins (such as alpha synuclein) in the spinal fluid and blood of Parkinson's patients at high risk of dementia, and is this a useful tool to help predict and track development of dementia? 3. Do these abnormal clumps of tau protein drive an inflammatory response in patients' immune cells? Answering these questions will bring us much closer to developing new treatments to prevent or slow the onset of the dementia which has such devastating consequences for patients with PD. It will also allow us to work out which combination of the tools we are studying (brain imaging, blood and spinal fluid tests) is most useful for tracking progression to dementia and the effect of treatments on this over time, which will be critical for future clinical trials of these treatments.