Prodromal Lewy Body Symptoms and α-Synuclein Seeding in Idiopathic Olfactory Dysfunction

Early identification of pathological α-synuclein deposition (αSynD) may improve understanding of Lewy body disorder (LBD) progression and enable timely disease-modifying treatments.

We investigated αSynD using a seed amplification assay and assessed prodromal LBD symptoms in individuals with idiopathic olfactory dysfunction (iOD).

In this cross-sectional, case-control study, we included iOD participants and normosmic healthy controls (HC) aged 55 to 75 years without diagnoses of dementia with Lewy bodies, Parkinson's disease (PD), or other major neurological disorders. iOD was defined as hyposmia without any known causes. The primary outcome was αSynD detection in skin and olfactory mucosa. Secondary outcomes included prodromal LBD symptoms: cognitive dysfunction, rapid eye movement sleep behavior disorder (RBD), motor and nonmotor symptoms (Movement Disorders Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Parts I-III), and prodromal PD risk.

We recruited 44 iOD participants (mean age 65) and 50 HCs (mean age 67). Eighteen iOD participants (41%) were αSynD positive in skin and/or olfactory mucosa compared to 1 HC (2%, P < 0.0001). iOD participants had higher rates of cognitive dysfunction (48% vs. 24%, P = 0.02), possible RBD (41% vs. 16%, P = 0.01), and elevated MDS-UPDRS I-III (median [interquartile range]: 15 [7-22] vs. 5.5 [3-11], P < 0.0001). Dysautonomia symptoms did not differ significantly. In the iOD group, 45% met probable/possible prodromal PD criteria versus 1 control (P < 0.0001). However, αSynD-αSynD-negative iOD participants had a nonsignificantly higher prodromal PD risk compared to αSynD-positive individuals.

iOD exhibits high αSynD prevalence and prodromal LBD symptoms, supporting its role as an early LBD marker and potential model for early intervention and mechanistic studies.