Peripheral Immune Alterations and T Cell Clonal Dynamics Across the Parkinson’s Disease Spectrum
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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.
Source: medRxiv
Authors: Mikaela Rosen, J. Oriol Narcis Majos, Daniele Mattei, Elena Mejia, Carlos Perez Mandry, Beomjin Jang, Kailash BP, Tatsuhiko Naito, Amanda Allan, Tarek Khashan, Charlie Argyrou, Mengxi Yang, Deborah Raymond, Casey Young, Kelly Astudillo, Aloysius Domingo, Steven Frucht, Susan Bressman, Anna Tocheva, Giulietta Riboldi, Rachel Saunders-Pullman, Towfique Raj
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Evaluation of glucocerebrosidase pathway biomarkers in Parkinson Disease, The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome, G2496204863, Learning the Regulatory Code of Alzheimer's Disease Genomes, G3194319764, Transforming Genomics with 5 PB Big Omics Data Engine Cray CS300-AC Supercomputer, The role of peripheral myeloid cells in Alzheimers disease, Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease, Big Omics Data Engine 2 Supercomputer, G4405376920, G6177305277, The Role of Alternative Splicing in Neurodegeneration, COVID and Translational Science supercomputer (CATS), G8556467429, Early Onset Parkinson’s disease subtypes and pathogenic mechanisms, Conduits: Mount Sinai Health System Translational Science Hub, Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets, Mount Sinai Alzheimer's Disease Research Center, Role of T-lymphocytes in Idiopathic and Genetic Parkinson's Disease, Modeling the impact of regulatory and splicing variants on cellular function in Alzheimer's disease, The Role of Myeloid Cells in Parkinson's Disease
OpenAlex ID: W7215063556