![]() Recently, highly sensitive seed amplification assays (SAA) exploiting the seeding capacities of prion and prion-like proteins as an amplification strategy to reveal minute amounts of disease-specific protein aggregates in CSF and other accessible biomaterials 1, 2, 3, 4, 5, 6, 7 have shown high sensitivity (86–96%) and specificity (83–100%) for sporadic PD and dementia with Lewy bodies (DLB) compared to healthy individuals 8, 9. With disease-modifying compounds such as monoclonal antibodies or active vaccination targeting α-Syn currently tested in clinical trials, patient stratification according to α-Syn-specific enrichment strategies is a much-needed prerequisite. Misfolded alpha-synuclein (α-Syn), the hallmark of the typical Lewy body pathology, is a lead candidate based on its crucial role in disease pathophysiology. The clinicopathological heterogeneity in Parkinson’s disease (PD) and the limitation of current clinical diagnostic criteria, especially at disease onset, highlight the need for pathology-specific biomarkers. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline. Results remained similar in separate subgroup analyses of patients with and without GBA mutation. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson’s disease with positive CSF alpha-synuclein seeding status. While the assays’ qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. Seed amplification assays have been implemented in Parkinson’s disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens.
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