Amplification parameters of the alpha-synuclein seed amplification assay on CSF predict the clinical subtype of Parkinson's Disease at 10-year follow-up.

Importance: Data-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM) and Diffuse Malignant (DM) as subtypes of Parkinson's Disease (PD) with a different degree of motor and non-motor impairment at time of diagnosis. It is not clear whether subtypes remain stable over time nor whether they represent distinct biological substrates. The recent introduction of alpha-synuclein seed amplification assay on CSF (CSF-αSyn-SAA) might provide further insights.

Objective: To assess the association between the parameters of CSF-αSyn-SAA collected at baseline and the clinical evolution of PD subtypes for 10 years.

Design: Retrospective, longitudinal, cohort study.

Setting: Data were collected from the Parkinson's Progression Marker Initiative (PPMI) cohort.

Participants: Subjects with a sporadic form of PD and positivity on CSF-αSyn-SAA (n=323) were included.

Exposure: clinical and biochemical data available in the PPMI dataset.

Main outcome and measure: PD participants were classified as MMP, IM and DM at baseline (n=323) and 10-year follow-up (n=146), based on previously published motor summary score and three non-motor features (cognitive impairment, RBD and dysautonomia). CSF-αSyn-SAA parameters were collected at baseline, including Fmax (maximum fluorescence), T50 (time to reach 50% of Fmax), TTT (time to threshold), Slope, and AUC (area under the curve). CSF Aβ1-42, tTau, pTau181, CSF and serum NfL were also collected at baseline.

Results: Times of reaction ( T50 and TTT) and AUC respectively were shorter and larger in DM subtype compared to IM/MMP subtype. The difference in amplification parameters at baseline was more evident when comparing subtypes based on the 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 the baseline clinical features (T50, η2=0.012; TTT, η2=0.012; AUC, η2=0.013; all p<0.05). Shorter T50 and TTT assessed at baseline were associated with a greater risk of DM subtype versus MMP at 10-year follow-up (T50, OR=3.286, p=0.010; TTT, OR=4.586, p=0.001). CSF Aβ1-42, tTau, pTau181, CSF and Serum NfL did not differ between groups.

Conclusions and relevance: CSF-αSyn-SAA parameters collected at baseline predicted the long-term progression of PD. In detail, faster reactions were associated with a severer 10-year phenotype of PD considering motor, cognitive, sleep and dysautonomia features.

Key points: Question: Can the parameters of alpha-synuclein seed amplification assay on CSF (CSF-αSyn-SAA) predict the long-term evolution of Parkinson's Disease (PD) clinical subtypes?Findings: In this retrospective, longitudinal study including 323 PD subjects from the PPMI cohort, we found that faster CSF-αSyn-SAA reactions at baseline were associated with a greater risk of developing a diffuse malignant phenotype with severer motor, cognitive, sleep and dysautonomia features after 10 years.Meaning: CSF-αSyn-SAA parameters might predict the long-term clinical progression of PD.