Refining α-synucleinopathy risk in isolated REM sleep behavior disorder patients using repeated olfactory testing

Abstract

Objective This study investigated the prognostic utility of repeated olfactory testing in patients with isolated REM sleep behavior disorder (iRBD) for predicting phenoconversion to overt alpha-synucleinopathies. Methods We analyzed 59 iRBD patients (mean age: 66.9 +/- 7.2 years; 91.5 % male) who underwent olfactory testing using the University of Pennsylvania Smell Identification Test at baseline and at a two-year follow-up. Patients were classified into persistent hyposmia, persistent normosmia, or unstable olfactory function groups. Clinical, cognitive, and dopamine transporter single photon emission CT (DAT-SPECT) parameters were assessed longitudinally. Results Olfactory function remained stable in most patients. The persistent hyposmia group (n = 37, 62.7 %) exhibited higher age, worse DAT-SPECT indices, and significant progression in MDS-UPDRS III over two years. In contrast, the persistent normosmia group (n = 11, 18.6 %) showed no significant neurodegenerative changes and had a 0 % phenoconversion rate over similar to 5 years. Phenoconversion occurred in 20.3 % of patients, predominantly among those with persistent hyposmia (9/12 converters) and in patients from the unstable olfactory group (3/12 converts). While baseline hyposmia alone did not predict phenoconversion, repeated hyposmia significantly increased the risk (p < 0.05). Conclusion Repeated olfactory testing improves risk stratification in iRBD. Persistent normosmia is associated with a lower risk of phenoconversion, whereas persistent hyposmia predicts neurodegeneration. Serial olfactory assessments may serve as a cost-effective tool for identifying high-risk patients and refining recruitment for neuroprotective trials.