1. Investigate gene-environment interactions in PSP susceptibility
PSP is a rare neurodegenerative disease, and clinical evaluation has revealed a predisposition to familial inheritance (Farrell, K., 2024). Environmental factors such as alcohol consumption and exposure to industrial metals also play a role (Litvan, I., 2021). None of these risk factors have been identified as the ultimate cause of PSP. To characterize the combined effects of genetic risk variants and modifiable lifestyle factors (dietary patterns quantified by 24-hour recall, physical activity metrics, and vascular risk profiles) on PSP susceptibility, utilizing polygenic risk scores and gene-environment interaction analyses within UK Biobank’s GWAS data.
2. Elucidate neurovascular mediation mechanisms
High white matter intensity is considered a MRI biomarker for cerebral small vessel disease, while white matter degeneration is characteristic of PSP (Tepedino, M. F., 2024). However, studies on the association between white matter, the presence of vascular risk factors, and disease features in PSP are lacking. To delineate the mediating and moderating roles of CSVD markers, including white matter hyperintensity volume and cerebral microbleed prevalence, in translating genetic/environmental risks into PSP pathogenesis, employing causal mediation analysis with longitudinal adjustment.
3. Identify progression-predictive biomarkers
Diagnosis of PSP remains a major challenge. PSP doesn’t currently include biomarkers in their diagnostic criteria (Giannakis, A., 2025). To determine key prognostic factors influencing PSP progression heterogeneity, focusing on rate of cognitive decline and motor deterioration, through machine learning-driven trajectory clustering and time-to-event modeling.
