Study Rationale: Alpha-synuclein is a protein that forms clumps in the brain in Parkinson’s disease (PD). Although alpha-synuclein aggregation is a common cause of dementia, other proteins are also associated with dementia, for example amyloid-beta and tau. We now have sensitive tests called seeding assays which can be used to identify people with clumps of alpha-synuclein in the brain. However, the tests are so sensitive, that they may identify people with amounts of alpha-synuclein that are insufficient to cause dementia. For clinical trials, it is important to include only people with significant amounts of alpha-synuclein aggregation.
Hypothesis: We hypothesize that developing a method to identify people with significant amounts of alpha-synuclein in the brain and exclude those with only small amounts will allow us to better understand PD pathology and to develop effective treatments.
Study Design: Currently, the amount of alpha-synuclein in the brain can only be identified by looking at postmortem tissue. We will use cerebrospinal fluid that was taken after death from people who donated their brains to the UK Brains for Dementia Research program. We will determine whether changes to the seeding assay, measurement of other proteins in the CSF or the presence of certain clinical features during life can differentiate those with significant amounts of alpha-synuclein from those with much smaller amounts.
Impact on Diagnosis/Treatment of Parkinson’s disease: Including people with small amounts of alpha-synuclein in clinical trials will impede identification of effective treatments, as drugs targeting alpha-synuclein will not help these individuals. Accurately identifying people with significant amounts of alpha-synuclein will hasten the development of effective treatments for PD and associated disorders.
Next Steps for Development: If we can successfully identify people with significant amounts of alpha-synuclein, we will seek additional funding to test our method in independent postmortem cohorts, and then test it in cohorts of people who had cerebrospinal fluid sampled during life and who later donated their brains to brain tissue resources.