The PARK-SEED study: using seed amplification assays to enhance the diagnosis, prognosis and treatment of parkinsonian disorders

In the UK, approximately 150,000 people are living with Parkinson's disease (PD) and this is estimated to rise to around 175,000 people by 2030. Therefore, PD is a common and debilitating cause of morbidity and mortality in the UK, representing significant economic cost to the National Health Service. In current clinical practice, the diagnosis of PD is made by a physician-led clinical examination as there are no objective tests that reliably diagnose the condition. However, achieving an early and accurate clinical diagnosis of PD is challenging because at that stage there is significant clinical overlap with Parkinson-plus disorders, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which also lack objective diagnostic tests. Being able to accurately diagnose Parkinsonian disorders at an early disease stage is important because it removes diagnostic uncertainty for patients. It also enables patients to be recruited to clinical trials at a stage in their disease when minimal irreversible damage has occurred, therefore representing a window of opportunity for effective drugs to stop or slow disease progression. The primary neuropathology of PD and MSA is characterised by a build-up of pathological forms of alpha-synuclein protein (Lewy bodies) in brain cells which leads to progressive brain cell loss and associated symptoms of PD. Of note, secondary Lewy body co-pathology can be found in other neurodegenerative disorders. In contrast, brain cell loss in PSP is associated with a build-up of pathological 4-repeat tau (4RT) protein in brain cells, and this never occurs as a co-pathology in other neurodegenerative disorders. Recently, an alpha-synuclein seed amplification assay (SAA) test has been developed. When applied to patient CSF samples, it reliably detects the presence of alpha-synuclein related PD pathology at the earliest stages of disease, and may even enable differentiation between PD- and MSA-type alpha-synuclein pathology. However, our own recent work has shown that the CSF alpha-synuclein SAA is also positive in a subset of PSP patient samples, likely due to alpha-synuclein co-pathology which may impact on disease trajectory. Therefore, using alpha-synuclein SAA in isolation as a diagnostic biomarker cannot reliably differentiate between PD and PSP. As such, there is a need to develop a 4RT tau SAA (which we expect to only be positive in PSP CSF samples) to use in combination with alpha-synuclein SAA for accurate diagnostic differentiation between PD, MSA and PSP. Accordingly, we have developed a novel 4RT SAA and are currently optimising its application to CSF samples. In this project we aim to: 1) apply alpha-synuclein and 4RT SAAs in combination to CSF samples from patients with: a) clinically established PD and PSP; b) early symptoms of an underlying Parkinsonian disorder that is clinically indeterminate. 2) assess whether quantitative kinetic measures that are derived from the alpha-synuclein and 4RT SAA tests (in combination with other biomarkers of interest) can predict and/or track clinical disease progression in PD and PSP. 3) use SAA kinetic measures as quantitative traits in separate genome-wide association studies of PD and PSP. This ambitious project has the potential to address major unmet needs for patients with parkinsonian disorders. Primarily, our results will provide evidence for combining alpha-synuclein and 4RT SAA testing for early and accurate diagnosis and prognosis of PD and PSP. Furthermore, our approach of integrating SAA kinetic measures and genetic data has the potential to identify novel treatment targets.