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. 2025 Mar 11;104(5):e210279.
doi: 10.1212/WNL.0000000000210279. Epub 2025 Feb 6.

α-Synuclein Seed Amplification Assay Amplification Parameters and the Risk of Progression in Prodromal Parkinson Disease

David G Coughlin  1 , Ben Shifflett  2 , Carly M Farris  3 , Yihua Ma  3 , Douglas Galasko  1 , Steven D Edland  1 , Brit Mollenhauer  4 , Michael C Brumm  5 , Kathleen L Poston  6 , Kenneth Marek  7 , Andrew D Siderowf  8 , Claudio Soto  9 , Luis Concha-Marambio  3 ; as the Investigators of the Parkinson's Progression Marker Initiative
Affiliations

α-Synuclein Seed Amplification Assay Amplification Parameters and the Risk of Progression in Prodromal Parkinson Disease

David G Coughlin et al. Neurology. .

Abstract

Objectives: Tools are needed to evaluate the risk of developing Parkinson disease (PD) in at-risk populations. In this study, we examine differences in alpha-synuclein seed amplification assay (αSyn-SAA) qualitative results and amplification parameters between nonmanifesting carriers (NMCs) of PD-related pathogenic variants, prodromal PD, and PD and the risk of developing a synucleinopathy in participants with prodromal PD.

Methods: Cross-sectional and longitudinal CSF αSyn-SAA results from participants in the Parkinson's Progression Markers Initiative were analyzed. αSyn-SAA positivity and amplification parameters (maximum fluorescence [Fmax], time-to-threshold [TTT], time-to-50% Fmax [T50], and area under the curve [AUC]) were compared between NMCs, participants with prodromal PD, and participants with PD, and their relationship with the likelihood of phenoconversion in participants with prodromal PD was investigated.

Results: Samples from 1,027 participants were analyzed (159 healthy controls [HCs], 247 NMCs, 96 participants with prodromal PD, and 525 participants with PD). TTT and T50 were faster, and AUC was higher in αSyn-SAA+ participants with prodromal PD and PD than αSyn-SAA+ NMCs and HC participants (Kruskal-Wallis χ2 = 4.15-13.96, p < 0.0002-0.04). Participants with prodromal PD with positive αSyn-SAA tests and faster TTT had higher rates of phenoconversion (log-rank p = 0.001 and log-rank test-for-trend p < 0.0001). There were no changes in 48 participants with prodromal PD with longitudinal assays.

Discussion: αSyn-SAA positivity and faster seed amplification are associated with a greater risk of developing PD in at-risk individuals and may aid in predicting phenoconversion.

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Conflict of interest statement

Y. Ma, C.M. Farris, C. Soto, and L. Concha-Marambio are Amprion employees and declare employee stock option ownership and invention of patents related to SAA assigned to Amprion. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. αSyn-SAA Amplification Parameters Across Cohorts
Baseline speed of αSyn-SAA amplification evaluated using TTT (h) for different cohorts. (A) TTT for all αSyn-SAA+ participants, including healthy controls, GBA and LRRK2 nonmanifesting carriers, prodromal PD, and PD. (B) TTT for αSyn-SAA+ participants with prodromal PD grouped by prodromal symptoms (hyposmia and RBD) compared with nonmanifesting carriers. (C) TTT for αSyn-SAA+ participants with PD by genetic status. (D) Correlations of different amplification parameters. Size of the circle indicated magnitude of the correlation along with color indicating direction of association. **p < 0.01 for Pearson correlation between amplification parameters. αSyn-SAA = alpha-synuclein seed amplification assay; AUC = area under the curve, Fmax = maximum fluorescence; PD = Parkinson disease; T50 = time-to-50% maximum fluorescence; TTT = time-to-threshold.
Figure 2
Figure 2. αSyn-SAA Positivity and Amplification Parameters and the Risk of Phenoconversion
(A) Participants with prodromal PD with positive αSyn-SAA had a greater likelihood of phenoconversion to PD or DLB. (B) Of those with positive αSyn-SAA tests, participants with prodromal PD with faster TTT (by median split) had the greatest likelihood of phenoconversion, followed by those with slower TTT values and participants with negative αSyn-SAA. αSyn-SAA = alpha-synuclein seed amplification assay; DLB = dementia with Lewy bodies; PD = Parkinson disease; TTT = time-to-threshold.
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References

    1. Shahnawaz M, Tokuda T, Waragai M, et al. . Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 2017;74(2):163-172. doi:10.1001/jamaneurol.2016.4547 - DOI - PubMed
    1. Rossi M, Candelise N, Baiardi S, et al. . Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140(1):49-62. doi:10.1007/s00401-020-02160-8 - DOI - PMC - PubMed
    1. Arnold MR, Coughlin DG, Brumbach BH, et al. . α-Synuclein seed amplification in CSF and brain from patients with different brain distributions of pathological α-synuclein in the context of co-pathology and non-LBD diagnoses. Ann Neurol. 2022;92(4):650-662. doi:10.1002/ANA.26453 - DOI - PMC - PubMed
    1. Siderowf A, Concha-Marambio L, Lafontant D-E, et al. . Assessment of heterogeneity among participants in the Parkinson's progression markers initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22(5):407-417. doi:10.1016/S1474-4422(23)00109-6 - DOI - PMC - PubMed
    1. Kang UJ, Boehme AK, Fairfoul G, et al. . Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease. Mov Disord. 2019;34(4):536-544. doi:10.1002/mds.27646 - DOI - PMC - PubMed