Study Rationale:
Parkinson’s disease (PD) is difficult to diagnose early and to distinguish from related synucleinopathies such as DLB and MSA. Although single-nucleus RNA sequencing reveals cell-type-specific changes in the PD brain and fluid proteomic and metabolomic studies identify accessible biomarkers, these data remain disconnected and fail to capture patient heterogeneity or disease progression. To address this gap, we developed Cell-Projected Phenotypes (CPP), which maps donor traits onto single-cell transcriptional neighborhoods to identify disease-associated states. By integrating brain transcriptomics with blood and CSF biomarkers and clinical data, we aim to derive mechanistically grounded, patient-level biomarkers for improved diagnosis, prognosis, and precision treatment.
Hypothesis:
Our hypothesis is that integrated analysis of peripheral biomarkers and brain transcriptional states can identify mechanistically interpretable molecular endotypes that differentially diagnose and predict clinical trajectories in Parkinson's disease and related synucleinopathies.
Study Design:
This study aims to combine two types of information: (1) detailed single-cell gene expression maps of individual brain cells from people with and without Parkinson’s, and (2) measurements from blood and spinal fluid that may reflect what is happening in the brain. Using advanced computer methods, we identify groups of cells and molecules that change together in Parkinson’s disease and link these patterns to symptoms and clinical outcomes. The goal is to create clear, biologically grounded tests that can improve diagnosis, prognosis, and treatment decisions.
Impact on Diagnosis/Treatment of Parkinson’s disease:
We aim to improve Parkinson’s diagnosis and treatment by creating precise molecular signatures and blood-based biomarkers that detect disease earlier, distinguish it from similar conditions, and track progression. These tools enable more accurate patient stratification, guide therapy selection, and accelerate the development and evaluation of new treatments in clinical trials.
Next Steps for Development:
The next steps toward clinical application include validating these biomarker signatures in independent and prospective patient cohorts, developing clinically deployable blood-based assays, and integrating the markers into clinical trials to improve diagnosis, patient stratification, and treatment monitoring. With further regulatory qualification and real-world testing, these biomarkers could ultimately guide earlier diagnosis and more personalized therapeutic decisions in Parkinson’s disease.