Cerebrospinal Fluid Inflammation in Prodromal Parkinson's Disease

We hypothesized that prodromal Parkinson's disease (PD), characterized by rapid eye movement sleep behavior disorder (RBD) and/or hyposmia, begins with inflammation in the central nervous system that evolves into neurodegeneration. We combined clinical phenotyping and proteomics with single-cell RNA sequencing of cerebrospinal fluid (CSF) and blood from individuals with RBD, PD, and healthy controls, with multiple sclerosis as a comparator. CSF immune cell numbers were increased in RBD, particularly in those with lower prodromal PD probability scores, a composite score associated with time to phenoconversion. In these participants, CSF macrophages showed enhanced TNF, IL-6/JAK/STAT3, and interferon-{gamma} signaling and predicted crosstalk with CD4+ T cells involving TNF, antigen presentation, and costimulatory pathways. CSF Macrophages resembled mouse dural macrophages and shared TNF signaling with gut immune cells from -synuclein mouse models. These findings uncover a stage-specific TNF-associated inflammation involving crosstalk between CSF Macrophages and CD4+ T cells in prodromal PD.