Objective: To assess the association between the parameters of alpha-synuclein seed amplification assay on CSF (CSF-αSyn-SAA) within 2 years from Parkinson’s disease (PD) onset and the clinical evolution of disease subtypes at 10-year follow-up.

Background: Data-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM) and Diffuse Malignant (DM) as subtypes of PD with a different degree of motor and non-motor impairment at diagnosis[1]. It is not clear whether subtypes remain stable over time nor whether they reflect a distinct biological substrate. The development of the CSF-αSyn-SAA might provide insights into this direction.

Method: The PPMI dataset was used (https://www.ppmi-info.org). Sporadic PD subjects were classified as MMP, IM and DM at baseline (n=323) and 10-year follow-up (n=146), based on previously published motor summary score and three non-motor features (cognitive impairment, RBD and dysautonomia). CSF-αSyn-SAA parameters were collected at baseline, including Fmax (maximum fluorescence), T50 (time to reach 50% of Fmax), TTT (time to threshold), Slope, and AUC (area under the curve) using a 150-hrs protocol. CSF Aβ1-42, tTau and pTau181, CSF and serum NfL were also considered at baseline.

Results: Times of reaction (T50 and TTT) and AUC were respectively shorter and larger from the more benign to the more aggressive PD subtype (MMP>IM>DM). The difference in amplification parameters at baseline was more evident when comparing subtypes based on the 10-year clinical features (T50, η2=0.036; TTT, η2=0.031; AUC, η2=0.033; all p values < 0.05) than when comparing subtypes based on the baseline clinical features (T50, η2=0.012; TTT, η2=0.012; AUC, η2=0.013; all p<0.05). Shorter T50 and TTT assessed at baseline were associated with a greater risk of being classified as DM versus MMP at 10-year follow-up (T50, OR=3.286; TTT, OR=4.586; all p<0.05). CSF Aβ1-42, tTau, pTau181, CSF and Serum NfL did not differ between groups.

Conclusion: CSF-αSyn-SAA parameters collected at baseline predicted the long-term progression of PD. In particular, faster reactions, which may reflect a greater burden of Lewy Body pathology at diagnosis, were associated with a more severe PD phenotype at 10-years follow-up considering motor, cognitive, sleep and dysautonomic features[2,3].

References: [1] Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain. 2017 Jul 1;140(7):1959-1976. doi: 10.1093/brain/awx118. PMID: 28549077.
[2] Grillo P, Concha-Marambio L, Pisani A, Riboldi GM, Kang UJ. Association between the Amplification Parameters of the α-Synuclein Seed Amplification Assay and Clinical and Genetic Subtypes of Parkinson’s Disease. Mov Disord. 2024 Dec 18. doi: 10.1002/mds.30085. Epub ahead of print. PMID: 39692283.
[3] Mastrangelo A, Mammana A, Hall S, Stomrud E, Zenesini C, Rossi M, Janelidze S, Ticca A, Palmqvist S, Magliocchetti F, Baiardi S, Mattsson-Carlgren N, Hansson O, Parchi P. Alpha-synuclein seed amplification assay longitudinal outcomes in Lewy body disease spectrum. Brain. 2024 Dec 17:awae405. doi: 10.1093/brain/awae405. Epub ahead of print. PMID: 39689039.

PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager

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MDS Abstracts - https://www.mdsabstracts.org/abstract/amplification-parameters-of-the-alpha-synuclein-seed-amplification-assay-on-csf-predict-the-clinical-subtype-of-parkinsons-disease-at-10-year-follow-up/