Predicting CSF α-Synuclein Seed Amplification Assay Status From Demographics and Clinical Data

Background and Objectives The alpha-synuclein (α-syn) CSF seed amplification assay (CSF SAA) presents a promising diagnostic for Parkinson disease (PD) and other synucleinopathies. The objective of this study was to develop and externally validate models to predict probabilities of α-syn positive or negative status in vivo in a mixture of people with and without PD using easily accessible clinical predictors. Methods Univariable and multivariable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict CSF α-syn status as measured by SAA. Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF α-syn status using SAA. Results The PPMI model training/testing cohort included 1,260 participants, 37% of whom were female, with a mean (± standard deviation) age of 62.4 (±10.0) years. Among them, 76% had manifest PD with a mean disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% of those with manifest PD) had positive CSF α-syn SAA status results. Variables from the full multivariable model to predict CSF α-syn SAA status included age-specific and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported frequency of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, and GBA status. Internal performance of the model on PPMI data to predict CSF α-syn SAA status showed an area under the receiver operating characteristic curve (AUROC) of 0.921 and a sensitivity/specificity of 0.858/0.868. This model was applied to the external S4 cohort, which included 71 participants, 39% of whom were female, with a mean age of 63.0 (±8.0) years, and included 70.4% with manifest PD (for a mean 5.1 (±4.8) years). The model performed well, achieving an AUROC of 0.978 and a sensitivity/specificity of 0.958/0.870. Discussion Data-driven models using noninvasive clinical features can accurately predict CSF α-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting α-syn SAA status.