Neuroprotective Trials in REM Sleep Behavior Disorder: The Way Forward Becomes Clearer

As neuroprotective therapies continue to be advanced against neurodegenerative synucleinopathies, such as Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system atrophy, increasing attention is turning to the prodromal stages of disease. Treatments at the prodromal stage have the compelling advantages of being applied early enough to make a meaningful difference and can be tested without confounding by symptomatic therapies used for clinical PD/DLB. As it currently stands, patients with idiopathic/isolated REM sleep behavior disorder (iRBD) represent the only large existing cohort of untreated prodromal PD/DLB that would be ready to start a clinical trial now. Several thousand patients with RBD are currently being followed in research-based clinics, and more than 80% of them will develop a full neurodegenerative synucleinopathy. Research into RBD phenoconversion rates and predictors has advanced considerably, and we are now able to generate increasingly precise estimates of progression rates, can select stratification markers to enrich trials, and are able to understand the progression and sample size implications of different primary outcome measures. This review will outline the potential for neuroprotective trials in iRBD, including the pathophysiologic mechanisms with the most promise to target in iRBD, selection criteria for inclusion, and the optimal primary trial outcome measures to choose.