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To test this hypothesis, we performed single-cell RNAseq analysis of cerebrospinal fluid (CSF) and blood from 118 individuals, comparing healthy subjects with prodromal PD and manifest PD to patients with the central nervous system (CNS) autoimmune disease, multiple sclerosis (MS). Surprisingly, we identified increased numbers of immune cells in the CSF of patients with prodromal PD. Single-cell RNA sequencing revealed increases in CSF-specific microglia-like macrophages with enhanced JAK-STAT and TNF\u03b1 signaling signatures in prodromal PD. CSF macrophages exhibited similar transcriptional profiles to dural macrophages and gut muscularis macrophages from \u03b1-synuclein-expressing PD model mice. Finally, shared memory T cell clones were found in humans between gut and CSF T cells. These findings uncover a myeloid-mediated TNF\u03b1 inflammatory process in the CNS of patients with prodromal PD, with an immunological linkage between the gut and the CNS.<\/jats:p>","DOI":"10.1101\/2025.05.16.654530","type":"posted-content","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:50:26Z","timestamp":1747875026000},"source":"Crossref","is-referenced-by-count":2,"title":["Myeloid-Driven Inflammation in Prodromal Parkinson\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9872-4909","authenticated-orcid":false,"given":"Yoshiaki","family":"Yasumizu","sequence":"first","affiliation":[{"name":"Department of Neurology, Yale School of Medicine, New Haven, CT, 06510, USA"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4061-5766","authenticated-orcid":false,"given":"M. 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