Peripheral Immune Alterations and T Cell Clonal Dynamics Across the Parkinson’s Disease Spectrum

The role of peripheral immunity in Parkinson’s disease (PD) remains incompletely understood. Here, we performed paired single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) profiling of 630k peripheral blood mononuclear cells (PBMCs) from 168 donors spanning idiopathic and genetic PD, prodromal PD, and healthy controls. We identify broad changes in immune-cell composition across the disease spectrum, including decreased naive B cells and increased naive CD8+ T cells in idiopathic PD. Transcriptional profiling reveals disease stage-dependent remodeling of mitochondrial and oxidative phosphorylation programs, with increased activity in prodromal disease followed by reduced activity in manifest PD, consistent with a transition in peripheral immune state during disease progression. High-resolution T cell analysis further identifies sex-dependent changes in cytotoxic CD8+ T-cell states and TCR clonal diversity. TCR motif analysis reveals disease-associated receptor groups with predicted specificities spanning PD-related, viral and autoimmune antigens. Together, these findings provide a comprehensive single-cell map of peripheral immune dysregulation in PD, defining dynamic and sex-dependent remodeling of peripheral immunity across the PD spectrum.