Project: Predicting Phenoconversion

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ABSTRACT: NAPS2 PROJECT – PREDICTING PHENOCONVERSION Rapid eye movement (REM) sleep behavior disorder RBD is a condition in which the muscular paralysis that accompanies REM sleep is lost, resulting in recurrent dream enactment behavior. RBD occurs in approximately 40% of patients with PD, 75% of DLB, and 80% of MSA. Idiopathic/Isolated RBD (i.e. without a known associated neurodegenerative disease) occurs in 1% of the population over 50. Landmark studies have suggested that >80% of individuals with this form of RBD in fact have prodromal synucleinopathy, and 6-10% will phenoconvert to PD, DLB, or MSA each year. RBD therefore represents an unprecedented opportunity to directly study early stages of PD, DLB and MSA in detail. Recognizing the importance of early intervention, the key federal agencies focused on neurodegenerative disease in the US have proposed high priority recommendations to study the preclinical and prodromal aspects of synucleinopathies to prepare for clinical trials. The North American Prodromal Synucleinopathy Consortium, Stage 2 (NAPS2) represents expanded and extended efforts of the original NAPS Consortium focused on RBD which began in 2018. In NAPS2, over 300 participants with RBD along with a subset of matched controls will be evaluated in a comprehensive and standardized manner, with the RBD participants undergoing longitudinal clinical, blood and CSF, polysomnographic, and neuroimaging studies. These data, samples and scans will be collected, processed and analyzed in the Cores to provide key variables for conducting hypothesis-driven analyses in the Project, with the focus on Predicting Phenoconversion. This project will therefore seek to address many critical scientific issues pertaining to RBD and neuroprotective clinical trial planning, including the following: 1) determining the degree and distribution of abnormalities in clinical measures, PSG and biofluid biomarkers among a large cohort of persons with RBD; 2) determining the conversion rate from RBD to an overt synucleinopathy, and to define predictive biomarkers of phenoconversion; 3) tracking change on clinical measures and biomarkers to develop progression biomarkers of synucleinopathy, and 4) combining data on phenoconversion, predictive biomarkers, and progression biomarkers to estimate sample size according to different patient selection criteria and primary outcomes for neuroprotective clinical trials in RBD.