ABSTRACT Increasing evidence indicates that neuroinflammation is not a simple consequence of neurodegeneration in Parkinson’s disease (PD), but an active process in disease progression. Thus, biomarkers capable of detecting, staging, and monitoring alterations in these pathways promise to significantly advance PD therapeutics. We recently developed a proteomic pipeline that leverages innovative network-based strategies to identify panels of cerebrospinal fluid (CSF) biomarkers reflective of brain-based pathophysiology in neurodegenerative disease, including inflammatory and immune-mediated processes. The application of this approach to the brain and CSF proteomes of Alzheimer’s disease (AD) yielded highly reproducible, disease-specific CSF panels of biomarkers linked to glial-mediated inflammation, endothelial humoral immunity, and myelin dysfunction. We hypothesize that PD similarly features unique protein signatures in CSF reflective of brain-based neuroinflammation and immune-mediated degeneration. Thus, we propose to utilize this network proteomics strategy to identify and validate promising CSF biomarkers of PD neuroinflammation. Aim 1 will comprise an unbiased network analysis of regional inflammatory dysfunction in the PD brain proteome, delineating protein alterations linked to immune-mediated processes in vulnerable regions. This network-based analysis will help unravel the complexities of inflammatory biology in the PD brain, distinguishing cell types (e.g., microglial, astrocytic, endothelial) and functional properties (e.g., humoral, innate, pro- or anti-inflammatory) significantly associated with disease. In Aim 2, we will then integrate these results with differential expression analysis of the PD CSF proteome to identify CSF biomarkers with links to these brain-based inflammatory pathways. We will prioritize biomarkers for further validation based on robustness and reproducibility of PD differential expression, disease- specificity for PD, strength of association with brain-based inflammation, and ease of detectability using high- throughput MS strategies. Future directions will include large-scale targeted MS validation of these prioritized biomarkers with the overarching goal of developing a multiplex assay of PD inflammation that can be used to diagnostically profile patients, monitor disease progression, individualize therapeutic strategies, and confirm drug target engagement.