Objective: To investigate the association between baseline α-synuclein seed amplification assay (SAA) parameters and clinical and biomarker features of Parkinson’s disease (PD) at baseline and after 10 years.

Background: α-Synuclein SAA is a promising PD diagnostic tool, but the clinical and pathological relevance of its kinetics remains unclear.

Method: Data from 78 SAA-positive PD individuals (1) (mean age 58±11; 63% male) was retrieved from the PPMI cohort (2), including baseline and 10-year longitudinal assessments of motor, non-motor, CSF, serum, and imaging biomarkers. CSF α-synuclein SAA kinetics were analyzed using a 24-hour amplification protocol. Participants were stratified into rapid/strong (high Fmax/AUC/slope) and slow/weak (low Fmax/AUC/slope) α-synuclein aggregators based on median values. Clinical subtypes were defined using established multi-domain criteria (3). Bivariate correlation, multivariate regression, and mixed-effects models assessed associations between baseline SAA kinetics and clinical/biomarker profiles over 10 years, adjusted for age.

Results: A steeper slope, larger AUC, and higher Fmax of baseline SAA-24-hour amplification correlated with lower RBDSQ (r=-0.305, p=0.007) and higher MoCA (r=0.247, p=0.029) at baseline, as well as lower RBDSQ (r=-0.415, p=0.003), higher MoCA (r=0.327, p=0.023), and lower MDS-UPDRS-II/III scores at year 5 (r=-0.342, p=0.015) and year 10 (r=-0.600, p=0.005), all age-adjusted. Rapid/strong aggregators were younger (55.9±13.4 vs 60.8±10.0, p=0.096). At year 10, 77.8% of slow/weak aggregators developed a diffuse-malignant subtype, while none remained mild motor-predominant. In contrast, only 6.7% of rapid/strong aggregators developed a diffuse-malignant subtype, with 53% remaining mild motor-predominant (age-adjusted p=0.005). Rapid/strong aggregators had 2.3-times lower CSF IgG4 (p<0.001), slower bilateral putamen and left caudate atrophy (p<0.016), and higher MoCA scores (28.3 vs. 23.2, p=0.003), findings confirmed in an age-matched sensitivity analysis.

Conclusion: Baseline αSyn-SAA 24-hour kinetics showed paradoxical but consistent associations with clinico-pathological markers, where greater or faster amplification correlated with better baseline clinical features, a less aggressive 10-year course, and a milder inflammatory and neurodegenerative profile.

References: 1. Ma Y, Farris CM, Weber S, Schade S, Nguyen H, Pérez-Soriano A, et al. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study. Lancet Neurol. 2024; 23(12): 1225-1237.
2. Marek K., Jennings D., Lasch S., Siderowf A., Tanner C., Simuni T. The Parkinson progression marker initiative (PPMI) Prog Neurobiol 2011; 95: 629–635.
3. Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain 2017; 140(7): 1959-1976.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/paradoxical-association-of-kinetics-of-%ce%b1-synuclein-seed-amplification-24-hrs-assay-and-clinico-pathological-markers-of-parkinsons-disease/