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 150-h 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, or larger AUC, were associated with greater risk of DM versus MMP at 10-year follow-up (T50, OR = 4.1, p = 0.004; TTT, OR = 5.5, p < 0.001; AUC, OR = 3.5, p = 0.010). 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.