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

• Published in: Nature communications Vol. 16; no. 1; pp. 7182 - 9
• Main Authors: Mastenbroek, Sophie E., Collij, Lyduine E., Vogel, Jacob W., Caldera, Serena, Serrano, Geidy E., Adler, Charles H., Vargiu, Claudia Marina, Palmqvist, Sebastian, Barkhof, Frederik, Parchi, Piero, Beach, Thomas G., Ossenkoppele, Rik, Hansson, Oskar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 692/53/2421; 692/699/375/346; 692/699/375/365/1283; 692/699/375/365/1718; Accuracy; Aged; Aged, 80 and over; alpha-Synuclein - cerebrospinal fluid; alpha-Synuclein - genetics; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnosis; Alzheimer Disease - pathology; Alzheimer's disease; Autopsies; Autopsy; Basal ganglia; Biomarkers; Brain; Brain - pathology; Central nervous system diseases; Cerebrospinal fluid; Disease; Female; Humanities and Social Sciences; Humans; In vivo methods and tests; Lewy bodies; Lewy Bodies - metabolism; Lewy Bodies - pathology; Lewy Body Disease - cerebrospinal fluid; Lewy Body Disease - diagnosis; Lewy Body Disease - pathology; Male; Middle Aged; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neuropathology; Nucleic Acid Amplification Techniques - methods; Parkinson's disease; Parkinsonian Disorders - cerebrospinal fluid; Parkinsonian Disorders - diagnosis; Parkinsonian Disorders - pathology; Pathology; Performance evaluation; Regression analysis; Science; Science (multidisciplinary); Smell - physiology; Subgroups; Synuclein; Workflow
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-62458-7

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. CSF α-synuclein seed amplification assays detect Lewy body pathology accurately but are invasive and costly. Here, the authors show that a two-step workflow using smell-function prescreening maintained 94% accuracy while reducing CSF testing by 43%.