Study Rationale: Identification of misfolded alpha-synuclein aggregates in postmortem brain samples remains a major histopathological hallmark for confirming the diagnosis of Parkinson’s disease (PD). Recently, alpha-synuclein seed-aggregation assays have demonstrated an ability to accurately diagnose PD from peripheral tissue samples. However, whether these assays can be quantified for monitoring and assessing disease progression, stages and prognosis has yet to be determined. This project aims to optimize quantitative analyses using the alpha-synuclein seed-aggregation assay and to identify the most sensitive, specific, reproducible and stage-appropriate samples for early diagnosis, monitoring disease progression and assessing disease prognosis.
Hypothesis: This study will determine whether alpha-synuclein seed-aggregation assays on skin samples can quantifiably assess PD disease severity and stage, and whether skin samples from different body areas will be more specific and sensitive than other biosamples.
Study Design: We will compare the alpha-synuclein seeding activity from a variety of biosamples— including skin, cerebrospinal fluid, saliva and tears—collected from people with PD in different disease stages and a group of age- and sex-matched healthy controls. We will run the analyses using the real-time quaking-induced conversion (RT-QuIC) assay and protein-misfolding cyclic amplification (PMCA) assay in three independent labs with extensive expertise in seed-aggregation assays to identify the most sensitive, specific, reproducible and stage-appropriate biosamples.
Impact on Diagnosis/Treatment of Parkinson’s disease: Optimization of a quantitative alpha-synuclein seed-aggregation assay and identification of a readily accessible specimen that shows the best sensitivity and specificity will facilitate early PD diagnosis and the assessment of therapeutic efficacy in clinical trials.
Next Steps for Development: We will apply our optimized skin assay as a diagnostic marker in large clinical PD cohorts such as the systemic synuclein sampling study (S4), which monitors PD progression, and in disease-modifying drug trials.