Characterization of patients with isolated REM sleep behavior disorder and cerebrospinal fluid α-synuclein negativity

Isolated REM sleep behavior disorder (IRBD) represents the prodromal phase of synucleinopathies. We investigated the characteristics of IRBD patients who tested negative for misfolded α-synuclein (αsyn) in CSF. CSF αsyn was analyzed by seed amplification assay (SAA) in 191 consecutive patients. Using logistic regression, demographic and clinical variables were compared between subjects with negative (αsyn-) and positive (αsyn+) αsyn. αsyn- occurred in 47 (24.61%) patients who were younger (p = 0.018), had less electromyographic REM sleep activity (p < 0.001), and more frequent normal DAT-SPECT (p < 0.001), normosmia (p < 0.001), major depressive disorder (p < 0.001) and antidepressant use (p < 0.001). After a mean follow-up of 5.35 years, 5 of 47 (10.64%) αsyn- patients and 61 of 144 (42.36%) αsyn+ patients developed Parkinson disease (PD) or dementia with Lewy bodies (DLB). Kaplan-Meier analysis showed αsyn- patients had a lower risk of developing PD and DLB (log-rank test p < 0.001; HR 5.355, 95% CI 1.945-14.742). CSF αsyn- occurs in IRBD patients with lower age, less synucleinopathy biomarkers and lower or delayed risk of developing PD and DLB. The cause of αsyn- in IRBD might include a very early synucleinopathy stage or a non-synucleinopathy condition (e.g., antidepressant side-effect). Our observation in IRBD might be important for design of neuroprotective trials targeting αsyn.