ABSTRACT: NAPS2 BIOFLUID CORE REM sleep behavior disorder (RBD) is commonly a prodromal manifestation of diseases defined by pathologic alpha-synuclein (aSyn) protein accumulation (synucleinopathies). A large percentage of RBD patients are eventually diagnosed with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with varying rates of disease progression. Development and validation of biomarkers for RBD can improve the efficiency of future clinical trials by providing quantitative metrics for target engagement and drug efficacy. In the North American Prodromal Synucleinopathy Consortium on RBD, Stage 2 (NAPS2), the aims of the Biofluid Core will be 1) to oversee and coordinate [along with the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD)] the collection, processing, and storage of serially collected plasma and cerebrospinal fluid (CSF) samples at the NAPS2 consortium Sites; 2) to perform assays of established neurodegenerative markers; and 3) to develop and test promising novel markers. The key biofluid markers include assays that correlate with neurodegeneration such as neurofilament light chain (NfL) in plasma and CSF and total tau in CSF, as well as measures that correlate with pathologic protein accumulation in CSF including total αSyn, oligomeric αSyn [including new protein misfolding cyclic amplification (PMCA) technology], Aβ42, Aβ40, and phosphorylated tau (p-tau181). Efforts on developing and testing promising novel markers will include exploration of catechols in the CSF, exploration of exosomal markers in plasma, and measurement of αSyn oligomers in CSF by real-time quaking-induced conversion (RT- QuIC). The Biofluid Core will ensure scientific rigor through standardization of biofluid collection and use of innovative, state-of-the-art biofluid assays performed at laboratories with extensive prior experience. The Core will be directed by leaders in biofluid discovery and validation in synucleinopathies and other neurodegenerative diseases. The Core leads have collaborated with NAPS investigators on prior research studies in RBD and other synucleinopathies, and their prior experience and guidance will ensure consistency and standardization of planned biofluid assays as part of this consortium. All proposed fluid biomarker assays are backed by preliminary data and sound scientific evidence supporting their value in synucleinopathies. The Core will work closely with the Administrative, Clinical, and Database Management and Statistics (DMS) Cores, and along with the Genetics, PSG and Neuroimaging Cores, supply processed cross-sectional and longitudinal data of selected markers for the Project focused on predicting phenoconversion. The Core will also provide anonymized cross-sectional and longitudinal data for sharing with outside investigators.