PROJECT SUMMARY/ABSTRACT Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) comprise a group of neurodegenerative diseases that share the pathophysiological mechanism of abnormal aggregation of alpha-synuclein (?Syn). Promising attempts at disease modification in established synucleinopathies have failed, raising the important issue that patients who have clinically overt, established disease are too advanced for disease-modifying therapies to be efficacious. Therefore, strategies have evolved to allow for earlier disease detection and confirmation which was pursued in our current grant period with focus on pure autonomic failure (PAF). PAF has more recently been established as one of the synucleinopathies, and is characterized by isolated autonomic failure without motor or cognitive deficits, representing a pre-motor stage with high risk of conversion to MSA, PD, or DLB. The main goal of the current grant period was to identify and validate spinal fluid (CSF) and MRI biomarkers of conversion of PAF to motor synucleinopathies. We have accomplished that goal by identifying highly predictive mechanism-based CSF and MRI markers in established synucleinopathies, that when applied to the pre-motor stage can predict conversion and conversion phenotype. REM sleep behavior disorder (RBD) is a condition with close association with synucleinopathies and frequently presents as isolated RBD (iRBD) years before motor or cognitive symptoms develop. The relevance and implications of iRBD as prodromal synucleinopathy has been well recognized, but to date there are no reliable predictors of conversion, phenotype of conversion, or timing of conversion to an established synucleinopathy. We have expanded the biomarkers developed to predict PAF phenoconversion to iRBD patients and identified discrete CSF profiles akin to those seen in PAF and in manifest motor and cognitive synucleinopathies, so that we are now in a position to test the biomarker potential of these markers at the prodromal stage. In this renewal, we shall study sleep-study confirmed iRBD patients stratified by baseline CSF biomarker phenotype (MSA-, PD/DLB, or normal type) along with healthy control subjects with serial clinical evaluations combined with autonomic, CSF, and MRI biomarker studies. We will enhance the feasibility of reaching recruitment goals for each biomarker phenotype by enriching recruitment with participants in the North American Prodromal Synucleinopathy Consortium identified as biomarker phenotype required to reach our recruitment goals. Secondly, we will continue to follow PAF patients enrolled during the current grant period who have not yet phenoconverted to solidify the predictive value of developed biomarkers. The findings from this renewal proposal should result in establishing biomarkers for the pre-motor and prodromal stages of syncucleinopathies, which may translate to disease-modifying therapy trials standing a better chance at demonstrating efficacy, and which may eventually even allow for diagnosing selected neurodegenerative diseases at the preclinical stage.
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