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Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants
Andrea Mastrangelo, Serena Caldera, Sophie E Mastenbroek, Erica Vittoriosi, Shorena Janelidze, Geidy E. Serrano, Alireza Atri, Holly A. Shill et al.. Acta Neuropathologica, 2025-06-23
Topic: Brain proteins, microglia and lab models
The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in log 10 SD/ml) differed significantly among participants at different LBD stages ( p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage ( p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = − 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79–0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.
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APA 7th
Mastrangelo, A., Caldera, S., Mastenbroek, S. E., Vittoriosi, E., Janelidze, S., Serrano, G. E., et al. (2025). Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants. Acta Neuropathologica. https://doi.org/10.1007/s00401-025-02904-4
Vancouver
Mastrangelo A, Caldera S, Mastenbroek SE, Vittoriosi E, Janelidze S, Serrano GE, et al. Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants. Acta Neuropathologica. 2025. doi:10.1007/s00401-025-02904-4. PMID: 40549179.
BibTeX
@article{mastrangelo2025-40549179,
author = {Mastrangelo, Andrea and Caldera, Serena and Mastenbroek, Sophie E and Vittoriosi, Erica and Janelidze, Shorena and Serrano, Geidy E. and Atri, Alireza and Shill, Holly A. and others},
title = {{Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants}},
journal = {Acta Neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02904-4},
pmid = {40549179},
url = {https://doi.org/10.1007/s00401-025-02904-4}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility.
- The SD50 values (expressed in log 10 SD/ml) differed significantly among participants at different LBD stages ( p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage ( p < 0.0001).
- The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001).
- The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores.
- These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD.
Why it matters
This study applied an endpoint dilution RT-QuIC assay to postmortem cerebrospinal fluid and found that seeding dose values differed significantly among Lewy body disease stages and correlated with pathology burden. It supports a biomarker for Lewy body pathology but does not offer a treatment or cure.
Study details
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta Neuropathologica) |
| Journal's citation record | 3 / 4 | Acta Neuropathologica: journal h-index 287 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 15 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 8.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 15 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Piero Parchi: h-index 84 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Lund University: institution h-index 1,119 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 10 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40549179) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1007/s00401-025-02904-4
- PubMed: 40549179
- Original source →
- Free full text: Acta Neuropathologica →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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