Estimating the sequence of biomarker changes in Parkinson's disease

Objective: To estimate the sequence of several common biomarker changes in Parkinson's disease (PD) using a novel data-driven method. Methods: We included 374 PD patients and 169 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI). Biomarkers, including the left putamen striatal binding ratio (SBR), right putamen SBR, left caudate SBR, right caudate SBR, cerebrospinal fluid (CSF) alpha-synuclein, and serum neurofilament light chain (NfL), were selected in our study. The discriminative event-based model (DEBM) was utilized to model the sequence of biomarker changes and establish the disease progression timeline. The estimated disease stages for each subject were obtained through cross-validation. The associations between the estimated disease stages and the clinical symptoms of PD were explored using Spearman's correlation. Results: The left putamen is the earliest biomarker to become abnormal among the selected biomarkers, followed by the right putamen, CSF alpha-synuclein, right caudate, left caudate, and serum NfL. The estimated disease stages are significantly different between PD and HC and yield a high accuracy for distinguishing PD from HC, with an area under the curve (AUC) of 0.98 (95% confidence interval 0.97-0.99), a sensitivity of 0.95, and a specificity of 0.92. Moreover, the estimated disease stages correlate with motor experiences of daily living, motor symptoms, autonomic dysfunction, and anxiety in PD patients. Conclusion: We determined the sequence of several common biomarker changes in PD using DEBM, providing data-driven evidence of the disease progression of PD.