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Faster α-synuclein seeding in cerebrospinal fluid signaled a higher risk of cognitive decline in Parkinson’s disease.
A study published in June 2025 issue of Lancet Neurology about α-synuclein seed amplification assay (SAA) as a diagnostic marker for Parkinson’s disease with limited to small, single-center studies over short follow-up periods.
Researchers evaluated the diagnostic and prognostic utility of quantitative cerebrospinal fluid α-synuclein SAA kinetic measures in Parkinson’s disease.
They analyzed individuals with Parkinson’s disease, progressive supranuclear palsy, and healthy controls enrolled in 3 cohorts: the UK parkinsonism cohort, the Parkinson’s Progression Markers Initiative (PPMI), and the Tübingen Parkinson’s disease cohort. Baseline CSF α-synuclein SAA and clinical data were collected between Jan 1, 2005, and Nov 1, 2023. Seeding kinetic measures—time to threshold (TTT), maximum Thioflavin T fluorescence (MaxThT), and area under the fluorescence curve (AUC)—were calculated for each SAA-positive sample. These measures were compared between sporadic Parkinson’s disease, progressive supranuclear palsy, and monogenic Parkinson’s disease. Time-to-event analyses were used to evaluate the predictive value of SAA kinetics for unfavorable outcomes, adjusting for age, sex, and disease duration at testing.
The results showed that data from 1,631 individuals were analyzed, including newly generated data [Parkinson’s disease, n=66; progressive supranuclear palsy, n=52; controls, n=9] and previously collected data from the PPM [Parkinson’s disease, n=1,036; controls, n=239] and Tübingen [Parkinson’s disease, n=229] cohorts. In the UK cohort, α-synuclein SAA was positive in 96% [n=63] of Parkinson’s disease samples and 15% [n=8] of progressive supranuclear palsy samples. Of the positive progressive supranuclear palsy samples, 75% [n=6] showed low MaxThT and high TTT, suggesting Lewy body co-pathology. The TTT was shorter in GBA1-related Parkinson’s disease than in sporadic cases in both PPMI (P=0.04) and Tübingen (P=0.01). In the PPMI cohort, 73% [n=593 of 810] of SAA-positive individuals with Parkinson’s disease experienced an unfavorable outcome over a median 4.5-year follow-up [IQR 2–9], TTT predicted cognitive decline [Montreal Cognitive Assessment score ≤21] in both the PPMI [n=824, hazard ratio (HR) 2.36 (95% CI 1.60–3.46), P=0.001] and Tübingen [n=135, HR 2.17 (1.07–4.41), P=0.03] cohorts, TTT also predicted cognitive decline in individuals with Alzheimer’s biomarker-negative in the PPMI cohort [n=355, HR 1.80 (95% CI 1.03–3.18), P=0.04].
Investigators concluded that α-synuclein SSA kinetic measures supported the diagnostic distinction between Parkinson’s disease and progressive supranuclear palsy with Lewy body co-pathology.
Source: thelancet.com/journals/laneur/article/PIIS1474-4422(25)00157-7/fulltext
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