Longitudinal Real‐Time Quaking‐Induced Conversion Analysis of Misfolded α‐Synuclein in Idiopathic Rapid Eye Movement Sleep Behavior Disorder Patients with Baseline Cerebrospinal Fluid Negativity

BACKGROUND: While most patients with idiopathic REM sleep behavior disorder (IRBD) show CSF misfolded α-synucleinpositivity, a subset tests negative with an uncertain underlying substrate that may include non-synucleinopathy conditions. OBJECTIVE AND METHODS: We performed a longitudinal study in polysomnography-confirmed IRBD patients with negative CSF α-synuclein at baseline (LP1) who underwent a second lumbar puncture (LP2). α-synuclein presence was determined by seed amplification assay. RESULTS: Among 43 αSyn -negative patients at LP1, 9 (20.9%) converted to αSyn positivity over a mean follow-up of 2.8 ± 2.3 years. At LP1, converters exhibited a higher burden of Parkinson's disease biomarkers, including hyposmia, abnormal dopamine transporter single-photon emission computed tomography (DAT-SPECT), and increased REM sleep electromyographic activity, compared with patients with persistent αSyn negativity. Longer intervals between LP1 and LP2 were associated with higher αSyn shifting to positivity. CONCLUSION: Serial CSF αSyn assessments may identify a very early synucleinopathy stage. This strategy may improve patient selection for disease-modifying trials targeting αSyn.