Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 8.
doi: 10.1002/mdc3.70333. Online ahead of print.

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

Oskar Hoffmann McWilliam  1 , Remarh Bsoul  2 , Gunhild Waldemar  1   3 , Steen Gregers Hasselbalch  1   3 , Anja Hvid Simonsen  1 , Marie Bruun  1   3 , Laura Storm Næsborg Andersen  1 , Christian von Buchwald  3   4 , Kasper Aanæs  3   4 , Christian K Pedersen  4 , Ida S B Andersen  4 , Magne Bech  4 , Clara Hageman Pinborg  4 , Aušrinė Areškevičiūtė  2 , Eva Løbner Lund  2   3 , Kristian Steen Frederiksen  1   3
Affiliations

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

Oskar Hoffmann McWilliam et al. Mov Disord Clin Pract. .

Abstract

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

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

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Parkinson's disease; dementia with Lewy bodies; hyposmia; olfactory dysfunction; prodromal α‐synucleinopathy; seed amplification assay.

PubMed Disclaimer

References

    1. Fereshtehnejad SM, Yao C, Pelletier A, Montplaisir JY, Gagnon JF, Postuma RB. Evolution of prodromal Parkinson's disease and dementia with Lewy bodies: a prospective study. Brain 2019;142:2051–2067.
    1. Donaghy PC, McKeith IG. The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis. Alzheimer's Res Ther 2014;6:1–12.
    1. Braak H, Rüb U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 2003;110:517–536.
    1. Mastenbroek SE, Vogel JW, Collij LE, et al. Disease progression modelling reveals heterogeneity in trajectories of Lewy‐type α‐synuclein pathology. Nat Commun 2024;15:5133. https://doi.org/10.1038/s41467-024-49402-x.
    1. Adler CH, Beach TG, Zhang N, et al. Unified staging system for Lewy body disorders: Clinicopathologic correlations and comparison to Braak staging. J Neuropathol Exp Neurol 2019;78:891–899.

LinkOut - more resources