{"doi":"10.1016/j.ebiom.2025.105866","title":"Baseline α-synuclein seeding activity and disease progression in sporadic and genetic Parkinson's disease in the PPMI cohort","abstract":"BACKGROUND: α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α-syn seeding activity and α-syn SAA kinetic parameters are associated with disease progression in sporadic PD, LRRK2-associated PD (LRRK2 PD), and GBA-associated PD (GBA PD). METHODS: We analysed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α-syn SAA results from 564 PPMI participants (n = 332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects models, adjusted for potential confounders, to test whether baseline α-syn SAA positivity (n = 315 sporadic PD, 111 LRRK2 PD, and 66 GBA PD) and α-syn SAA kinetic parameters are associated with PD progression. FINDINGS: While non-statistically significant, there was a trend towards faster motor decline in participants with α-syn SAA positive LRRK2 PD compared to those with α-syn SAA negative LRRK2 PD (MDS-UPDRS III points per year: 2.39 (95% confidence interval: 1.86-2.92) vs. 1.76 (0.93-2.60); difference = 0.63 (-0.29 to 1.55, p = 0.18). This trend appeared to be driven by R1441C/G + M1646T carriers (3.89 (1.22-6.55) vs. 0.31 (-1.32 to 1.93); difference = 3.58 (0.56-6.60, p = 0.02) and excluding them eliminated any trend (2.33 (1.79-2.86) vs. 2.26 (1.34-3.18); difference = 0.07 (-0.93 to 1.07, p = 0.89). Based on a clinically meaningful difference of 4.63 points we found no statistically significant or clinically meaningful difference in motor decline between α-syn SAA positive and α-syn SAA negative participants with sporadic PD (2.46 (2.20-2.72) vs. 2.39 (1.36-3.42); difference = 0.07 (-0.99 to 1.12), p = 0.90) or GBA PD (2.67 (1.91-3.44) vs. 2.40 (-0.18 to 4.99); difference = 0.27 (-2.42 to 2.96), p = 0.84). No statistically significant or clinically meaningful differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. Additionally, we found no clinically meaningful association between α-syn SAA kinetic parameters and PD progression. INTERPRETATION: We found no statistically significant associations between baseline α-syn seeding activity, α-syn SAA kinetic parameters, and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among α-syn seeding activity, disease heterogeneity, disease stage, and PD progression. FUNDING: This research was funded by Aligning Science Across Parkinson's grant ASAP-237603 through the Michael J. Fox Foundation for Parkinson's Research and by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke grants R01NS102735 and 5R01NS126260.","journal":"EBioMedicine","year":2025,"id":521806,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9325,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":663003,"name":"Xinyuan Zhang","orcid":"0000-0002-2974-8392","position":1,"is_corresponding":false},{"id":226503,"name":"Eric A. Macklin","orcid":"0000-0003-1618-3502","position":2,"is_corresponding":false},{"id":581539,"name":"Jian Wang","orcid":"0000-0003-2291-640X","position":3,"is_corresponding":false},{"id":891301,"name":"Armin Bayati","orcid":"0000-0002-5960-0479","position":4,"is_corresponding":false},{"id":1392720,"name":"Johannes M. Dijkstra","orcid":"0000-0001-7097-3826","position":5,"is_corresponding":false},{"id":1392721,"name":"Hirohisa Watanabe","orcid":"0000-0001-8553-8536","position":6,"is_corresponding":false},{"id":263854,"name":"Michael A. Schwarzschild","orcid":"0000-0001-6019-8280","position":7,"is_corresponding":false},{"id":511428,"name":"Marianna Cortese","orcid":"0000-0002-3665-2006","position":8,"is_corresponding":false},{"id":269896,"name":"Xuehong Zhang","orcid":"0000-0002-8260-8508","position":9,"is_corresponding":false},{"id":814253,"name":"Xiqun Chen","orcid":"0000-0001-8582-8891","position":10,"is_corresponding":false},{"id":1392719,"name":"Jackson G. Schumacher","orcid":"0009-0000-4227-4710","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:49:49.198144Z","pmid":"40773926","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}