Objective: To evaluate whether kinetic signatures from alpha-synuclein CSF seed amplification assays (aSynSAA) are generalizable among SAA-positive Parkinson’s Disease (PD) samples across previously published cohorts.

Background: aSyn-SAA is commonly interpreted as positive or negative, but recent studies suggest that kinetic and fluorescent features may provide unique signatures that differentiate between the major forms of primary parkinsonism (CBS/PSP vs. PD [1-4]; PD vs. MSA [5]). However, it is unknown to what degree kinetic signatures in PD are generalizable across different CSF seed amplification assays. Misinterpretation across study designs may lead to false classification into atypical forms of parkinsonism.

Method: Two datasets were analyzed for aSyn-SAA metrics (time-to-threshold [TTT], maximal fluorescence, area under the curve [AUC], replicate positivity, and plate identifiers). The PROSPECT-UK cohort contained 63 aSyn-SAA-positive Parkinson’s disease (PD) and 8 aSyn-SAA-positive progressive supranuclear palsy (PSP) cases [3]. The Parkinson’s Progression Markers Initiative (PPMI) cohort contained 423 aSyn-SAA-positive PD cases and 9 aSyn-SAA-positive controls [6]. Group comparisons were analyzed by Welch t-tests and MannWhitney tests. Inter-study comparability was assessed by comparing PD kinetic distributions across cohorts.

Results: Cross-cohort comparisons showed Fmax distributions were similar between PROSPECT-UK PD and PPMI PD samples, whereas absolute TTT and AUC differed markedly, consistent with inter-study differences in assay definition/scaling or preprocessing (figure 1). PPMI PD and positive controls showed no differences in kinetic measures (figure 2).

Conclusion: Cross-cohort reproducibility appears stronger for peak fluorescence than for TTT or AUC, which vary greatly in scale across cohorts, likely reflecting differences in assay techniques. These findings support cautious exploration of kinetic classifiers, with explicit run/batch modeling and metric harmonization required before pooling datasets or extending to broader multi-syndrome classification.

Figure1

Figure2

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4. Anastassiadis C, Martinez-Valbuena I, Vasilevskaya A, Thapa S, Hadian M, Morales-Rivero A, Mora-Fisher D, Salvo C, Taghdiri F, Sato C, Moreno D, Anor CJ, Misquitta K, Couto B, Tang-Wai DF, Lang AE, Fox SH, Rogaeva E, Kovacs GG, Tartaglia MC. CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders. Neurology. 2024 Sep 24;103(6):e209818. doi: 10.1212/WNL.0000000000209818. Epub 2024 Aug 29. PMID: 39208367.

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6. Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LMA, Hutten SJ, Sherer T, Marek K, Soto C; Parkinson’s Progression Markers Initiative. 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 May;22(5):407-417. doi: 10.1016/S1474-4422(23)00109-6. PMID: 37059509; PMCID: PMC10627170.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/kinetic-features-of-alpha-synuclein-positivity-in-csf-seed-amplification-in-parkinsons-disease-an-exploratory-cross-cohort-analysis/