0417 Preclinical Model to Test Potential Therapeutics to Prevent Phenoconversion of REM Sleep Behavior Disorder to Parkinson’s Disease After Neurotrauma

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Abstract Introduction Neurotrauma, including traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), often results in persistent sleep disturbances and impaired neurological function. This includes an increased frequency for REM sleep behavior disorder (RBD), characterized by abnormally elevated skeletal muscle activity (i.e., REM sleep without atonia; RSWA) and overt dream enactment during REM sleep. RBD is one of the earliest clinical manifestations of synucleinopathies, including Parkinson’s Disease (PD). Furthermore, the presence of both TBI and PTSD are significantly associated with an increased risk for later development of PD and related synucleinopathies. As the synucleinopathies progress, patients can develop parkinsonism characterized by impaired movements as well as a decline in cognition. No disease-modifying therapeutics to date have been successful in synucleinopathies. To address this gap, we designed a preclinical pipeline for evaluation of potential therapeutics using a mouse model of neurotrauma, RBD, and PD. Methods Mice underwent Single Prolonged Stress (SPS) and Controlled Cortical Impact (CCI) to model PTSD and TBI, respectively. Gait, sleep, and cognitive outcomes were evaluated across various cohorts and at three different time points following neurotrauma (2, 4 and 12 weeks) to assess the specific time course of biomarkers and disease progression. Results Our results reveal that SPS and CCI results in increased rates of EMG activity during REM sleep, consistent with RBD. REM sleep EMG activity was positively correlated with cognitive impairments as early as 2 weeks following neurotrauma. Furthermore, neurotrauma mice revealed gait and cognitive impairments consistent with a PD phenotype. Conclusion In summary, our preclinical pipeline for evaluation of potential therapeutics holds face validity to the human conditions of neurotrauma, RBD, and PD, resulting in time-dependent changes in gait and cognition. This model will be useful for future studies investigating potential therapeutic interventions, to attenuate synuclein pathogenesis associated with neurotrauma. Support (if any) NIH-NCCIH T32 AT002688 to LD, VA BLRD Merit Award 1I01BX006155, DoD PRP HT9425-24-1-0775

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