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