Utilizing Intraindividual Cognitive Variability to Predict Early Neuronal Synuclein Disease Progression.

Background: Neuronal synuclein disease (NSD) involves pathological α-synuclein presence and often dopaminergic dysfunction, initially preceding overt clinical symptoms. NSD-ISS identifies Stage 2A (no dopaminergic dysfunction) and 2B (dopaminergic dysfunction) as prodromal phases marked by subtle clinical signs without functional impairment. Intraindividual variability/dispersion (IIV-D), reflecting within-person inconsistency across cognitive tasks, has emerged as a potential marker of early neurodegenerative changes. Objectives: This study examined whether IIV-D differentiates NSD Stage 2 participants from healthy controls and predicts progression to more advanced NSD stages. Methods: Data from the Parkinson's Progression Markers Initiative were used to assess performance across 11 neuropsychological tests in 934 participants (832 Stage 2; 102 controls). IIV-D was quantified using the total coefficient of variation (CoV) and a domain-specific attention/executive CoV. Group comparisons and logistic regression assessed associations between IIV-D, clinical characteristics, and disease progression. Results: Stage 2 participants exhibited significantly greater CoV than controls ( Conclusions: IIV-D, particularly CoV, may be a sensitive cognitive marker of early NSD and predict short-term disease progression. Findings support integrating cognitive dispersion metrics into early detection strategies for prodromal synucleinopathies, though replication is needed to confirm generalizability and clinical utility.