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A Systematic Comparison of Alpha-Synuclein Seed Amplification Assays for Increasing Reproducibility

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Seed amplification assays (SAAs) enable ultrasensitive detection of misfolded α-synuclein across biofluids and tissues. Yet, heterogeneity in protocols limits cross-study comparability and clinical translation. Here, we review α-synuclein SAA methods and their performance across various biological matrices. We catalog key variables (e.g., human recombinant α-synuclein variants, buffers, salts, beads, shaking, incubation temperature) and outline pre-analytical factors that shape outcomes. We propose a prioritized framework of key analytical and pre-analytical variables most likely to influence assay reproducibility and clinical interpretation. We also outline minimal reporting criteria and practical quality-control checkpoints, and recommend multicenter interlaboratory proficiency testing as essential steps to accelerate the robust clinical and research implementation of α-synuclein SAAs.

Publication metadata

Author(s): Amaral-do-Nascimento M, Santos DF, Vieira TCRG, Outeiro TF

Publication type: Review

Publication status: Published

Journal: Annals of Clinical and Translational Neurology

Year: 2026

Volume: 13

Issue: 6

Pages: 1088-1105

Print publication date: 01/06/2026

Online publication date: 01/04/2026

Acceptance date: 13/03/2026

ISSN (print): 2328-9503

ISSN (electronic): 2328-9503

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/acn3.70384

DOI: 10.1002/acn3.70384

Data Access Statement: This manuscript is a systematic review and synthesis of previously published studies. No new primary datasets were generated. All data supporting the findings of this review are available within the article and its Supporting Information and/or the cited literature.

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