Faster reaction times of CSF Alpha-Synuclein Seed Amplification Assay predict the Diffuse Malignant subtype of Parkinson's Disease at 10-year follow-up.

Background: Data-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM), and Diffuse Malignant (DM) as Parkinson's Disease (PD) subtypes with different motor and non-motor impairment at diagnosis. It remains unclear whether these subtypes remain stable over time or whether they represent distinct biological substrates. The alpha-synuclein seed amplification assay in CSF (CSF-αSyn-SAA) might provide further insights. Objective: to evaluate the association between baseline CSF-αSyn-SAA parameters and 10-year clinical evolution of PD subtypes. Methods: 323 sporadic PD patients from PPMI dataset were classified as MMP, IM, or DM at baseline and 10-year follow-up based on motor, cognitive, sleep and dysautonomia features. CSF-αSyn-SAA parameters were collected at baseline using a 150-hrs protocol. CSF Aβ1-42, tTau and pTau181, CSF and serum NfL were also considered at baseline. Results: Reaction times (T50, TTT) and area under the curve (AUC) respectively were shorter and larger in DM compared to IM/MMP. The difference in baseline amplification parameters was more evident when comparing subtypes based on 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 baseline clinical features (T50, η2=0.012; TTT, η2=0.012; AUC, η2=0.013; all p<0.05). Shorter T50 and TTT at baseline were associated with greater risk of DM versus MMP at 10-year follow-up (T50, OR=3.3, 95%CI: 1.3-8.1, p=0.010; TTT, OR=4.6, 95%CI: 1.8-11.6, p=0.001). Aβ, Tau and NfL were similar between groups. Conclusions: Baseline CSF-αSyn-SAA parameters predicted long-term PD progression. Faster reactions were associated with a more severe 10-year PD phenotype considering motor and non-motor features.