Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification

Sophie E. Mastenbroek (), Lyduine E. Collij, Jacob W. Vogel, Serena Caldera, Geidy E. Serrano, Charles H. Adler, Claudia Marina Vargiu, Sebastian Palmqvist, Frederik Barkhof, Piero Parchi, Thomas G. Beach, Rik Ossenkoppele and Oskar Hansson ()
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Sophie E. Mastenbroek: Lund University
Lyduine E. Collij: Lund University
Jacob W. Vogel: Lund University
Serena Caldera: IRCCS Istituto delle Scienze Neurologiche di Bologna
Geidy E. Serrano: Banner Sun Health Research Institute
Charles H. Adler: Mayo Clinic
Claudia Marina Vargiu: IRCCS Istituto delle Scienze Neurologiche di Bologna
Sebastian Palmqvist: Lund University
Frederik Barkhof: Amsterdam University Medical Center location VUmc
Piero Parchi: IRCCS Istituto delle Scienze Neurologiche di Bologna
Thomas G. Beach: Banner Sun Health Research Institute
Rik Ossenkoppele: Lund University
Oskar Hansson: Lund University

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assays (SAAs) can detect Lewy body pathology (LBP) with high accuracy but are invasive and costly. To address these challenges, this study evaluated a two-step workflow combining prescreening via smell-function testing with confirmatory CSF α-syn SAA testing only in individuals with reduced smell, for predicting postmortem LBP status. Among 358 autopsied participants, the two-step workflow predicted brain LBP with high accuracy overall (94%), and within clinical subgroups (clinical parkinsonism=95%; clinical Alzheimer’s disease [AD]=94%; clinically unimpaired [CU]=93%). It reduced the need for confirmatory CSF testing by 43% overall (23% clinical parkinsonism; 35% clinical AD; 80% CU). In an independent in vivo cohort (N=1209), the workflow predicted CSF α-syn SAA status with 79% accuracy and reduced CSF testing by 26%. This approach may reduce invasive CSF testing, alleviating patient burden and lowering healthcare costs.

Date: 2025
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DOI: 10.1038/s41467-025-62458-7

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