Smell testing to identify early alpha-synucleinopathy among people with dream enactment behavior

ABSTRACT Background REM sleep behavior disorder (RBD) is an early manifestation of alpha-synucleinopathy in many cases. Dream enactment behavior (DEB), the clinical hallmark of RBD, has many etiologies and cannot be used alone to predict underlying alpha-synucleinopathy. We compared the proportion of people with alpha-synucleinopathy, as measured by CSF alpha-synuclein seed amplification assay (CSFasynSAA), between people with polysomnographic-confirmed RBD (RBD-PSG) and people who reported DEB on a questionnaire and were further selected with smell testing and DAT-SPECT. Methods Participants were enrolled in the Parkinson’s Progression Marker Initiative (PPMI) and ≥60 years old without a diagnosis of Parkinson’s disease. Participants had either RBD-PSG or self-reported DEB. Self-reported DEB participants had to have hyposmia (<10 th percentile for age/sex) and at least mild DAT-SPECT abnormality (<100% age/sex-expected). We compared CSFasynSAA between RBD-PSG and self-reported DEB with hyposmia (DEB+Hypos). RBD-PSG participants also underwent smell testing and DAT-SPECT; we determined the predictive value of these tests in RBD-PSG with regards to CSFasynSAA. Results CSFasynSAA was positive in 171/240 (71%) of RBD-PSG and %) 180/210 (86%) of DEB+Hypos participants. Among RBD-PSG, hyposmia strongly predicted CSFasynSAA+ (PPV: 92% [95% CI 87%-97%]). Smell identification was more accurate than DAT-SPECT in predicting CSFasynSAA+ in RBD-PSG (AUC for UPSIT: 0.89 [95% CI 0.84 – 0.94]; AUC for DAT-SPECT: 0.65 [95% CI 0.58 – 0.73]). Conclusions Smell testing may be an effective and scalable method to identify people with alpha-synucleinopathy among those with self-reported DEB. Among individuals with RBD diagnosed by PSG, smell testing improved prediction of positive CSF alpha-synuclein biomarker.