Study Rationale: Normally folded a-synuclein protein is vital to normal brain function. However, misfolded a-synuclein can form the aggregated fibrils that contribute to Parkinson’s disease’s (PD) hallmark symptoms. Discovering a quantitative biomarker that can be safely sampled from biofluids or peripheral tissue biopsies would be immensely beneficial in diagnosing PD and monitoring its progression. When we adapted a new RT-QuIC protein misfolding assay to analyze samples biopsied from the submandibular gland (SMG) for the presence of misfolded a- synuclein, it distinguished between PD and healthy subjects with high diagnostic accuracy. To better validate RT-QuIC as a potential PD biomarker tool, we propose blind testing of SMG and CSF samples from S4 subjects.
Hypothesis: We hypothesize that the amount of misfolded aSyn detected in biofluids and peripheral tissue biopsies will serve as a diagnostic biomarker to identify PD and will correlate with the severity of disease progression as indicated by higher UPDRS scores and lower DAT and MMSE scores.
Study Design: This study seeks to determine the clinical utility and to compare the performance of our α- synuclein RT-QuIC assay via blind testing of both the SMG biopsies and CSF samples from the well-designed S4 PD cohorts study. There will be two groups, one consist of PD patients with different aSyn fiber densities (n=18 early, 20 moderate, and 21 advanced) and one consist of healthy controls (HC, n=21) without aSyn fibers. We will initially subject a subset of 3 samples from each group for RT-QuIC standardization and optimization. Afterwards, we will perform the RT-QuIC assay with all the remaining samples and subjects from the S4 study.
Impact on Diagnosis/Treatment of Parkinson’s disease: Detection of ultra-low levels of pathological α-synuclein in peripheral biopsies and biofluids collected from live patients would be a promising approach to improving the early diagnosis of PD as well as for monitoring disease progression and therapeutic efficacy.
Next Steps for Development: If successful, we would like to extend our α-synuclein RT-QuIC assay to other well- designed PD cohorts to increase sample size. After which, we will recommend this assay for clinical diagnosis of early PD, allowing neurologists to consider early therapeutic intervention to slow down or delay the progression of the disease.