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

Mastenbroek, Sophie E. LU ; Collij, Lyduine E. LU ; Vogel, Jacob W. LU ; Caldera, Serena ; Serrano, Geidy E. ; Adler, Charles H. ; Vargiu, Claudia Marina ; Palmqvist, Sebastian LU orcid ; Barkhof, Frederik and Parchi, Piero , et al. (2025) In Nature Communications 16(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
7182
publisher
Nature Publishing Group
external identifiers
  • scopus:105012622846
  • pmid:40764485
ISSN
2041-1723
DOI
10.1038/s41467-025-62458-7
language
English
LU publication?
yes
id
c31d4491-c68b-4084-a227-27884d0a9c65
date added to LUP
2025-10-22 08:34:32
date last changed
2025-11-19 10:37:59
@article{c31d4491-c68b-4084-a227-27884d0a9c65,
  abstract     = {{<p>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.</p>}},
  author       = {{Mastenbroek, Sophie E. and Collij, Lyduine E. and Vogel, Jacob W. and Caldera, Serena and Serrano, Geidy E. and Adler, Charles H. and Vargiu, Claudia Marina and Palmqvist, Sebastian and Barkhof, Frederik and Parchi, Piero and Beach, Thomas G. and Ossenkoppele, Rik and Hansson, Oskar}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-62458-7}},
  doi          = {{10.1038/s41467-025-62458-7}},
  volume       = {{16}},
  year         = {{2025}},
}