Olfactory impairment and probable REM sleep behavior disorder in Parkinson’s disease: clinical relevance to the single- and dual-hit hypotheses

Abstract

Rapid eye movement (REM) sleep behavior disorder (RBD) and olfactory impairment are common prodromal features of Parkinson’s disease (PD), but the implications of their coexistence remain uncertain. The dual-hit hypothesis proposes concomitant olfactory and enteric involvement, whereas the revised single-hit framework proposes predominantly brain-first or body-first routes. We examined whether probable RBD (pRBD)/anosmia-defined subgroups exhibit distinct clinical profiles. In this cross-sectional study, 201 individuals with PD underwent olfactory, cognitive, motor, non-motor, and quality-of-life assessments. Anosmia was defined as a University of Pennsylvania Smell Identification Test score <19 and pRBD as an RBD Screening Questionnaire score ≥6 supplemented by participant and informant interviews. Multivariable models evaluated the main and interactive effects of anosmia and pRBD. Of 201 participants, 95 (47.3%) were pRBD-positive (pRBD+), 135 (67.2%) had anosmia, and 68 (33.8%) had both. Anosmia prevalence did not differ between the pRBD+ and pRBD-negative (pRBD−) groups (71.6% vs. 63.2%; p = 0.208). After adjustment for age, sex, and disease duration, pR+A+ and pR+A− (subgroups defined by probable RBD status [pR+/pR−] and anosmia status [A+/A−]) did not differ in any assessed outcome. The anosmia-by-pRBD interaction was negative for MDS-UPDRS part III (β = −8.3, 95% CI −15.2 to −1.4; p = 0.019). Within the pRBD− subgroup, pR−A+ participants had lower MoCA scores than pR−A− participants (β = −2.6; 95% CI −4.1 to −1.0; p = 0.001), and the anosmia-by-pRBD interaction was positive for MoCA (β = 2.3, 95% CI 0.0 to 4.5; p = 0.049). Anosmia was associated with cognitive impairment in pRBD− participants (OR 2.53, 95% CI 1.00–6.37; p = 0.049), but not in pRBD+ participants (OR 1.65, 95% CI 0.60–4.50; p = 0.331). In pRBD+ participants, anosmia was not associated with greater motor severity; in pRBD− participants, it was instead linked to cognitive impairment. Concurrent assessment of olfaction and pRBD may improve clinical phenotyping, but longitudinal validation is required.