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
Gerard Mayà, Angelica Montini, Alice Ticca, Mónica Serradell, Angela Mammana, Noelia Caballero, Agustina Ranieri, Carles Gaig, Andrea Mastrangelo, Piero Parchi, Alex IranzoAbstract
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. © 2026 International Parkinson and Movement Disorder Society.