Utilizing intraindividual cognitive variability to predict progression in stage 2 neuronal synuclein disease

Neuronal synuclein disease (NSD) involves pathological α-synuclein presence and often dopaminergic dysfunction, initially preceding overt clinical symptoms. NSD-Integrated Staging System 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 the degree of spread in a person's performance across a battery of cognitive tasks, has emerged as a potential marker of early neurodegenerative changes. This study examined whether IIV-D differentiates NSD Stage 2 participants from healthy controls and predicts progression to more advanced NSD stages.

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 primarily quantified using the total coefficient of variation (CoV) and a domain-specific attention/executive CoV. Secondary exploratory analyses examined total intraindividual standard deviation (iSD) and attention/executive iSD. Group comparisons and logistic regression assessed associations between IIV-D, clinical characteristics, and disease progression.

Stage 2 participants exhibited significantly greater CoV (p = .003) and iSD (p < .001) than controls. Higher CoV was associated with worse motor symptoms, nonmotor burden, and functional impairment. Among Stage 2 participants, subsequent converters to Stage 3+ (n = 100) had significantly higher total CoV (p = .008) and attention/executive CoV (p = .020) at baseline. CoV independently predicted conversion after 1 year (OR = 1.44, p = .008), controlling for baseline motor severity. By contrast, neither iSD nor attention/exeutive iSD predicted progression in analogous models.

IIV-D, particularly CoV, may be a sensitive cognitive marker of early NSD and predict short-term disease progression. Measures of iSD did not demonstrate predictive utility. Findings support integrating cognitive dispersion metrics into early detection strategies for prodromal synucleinopathies, though replication is needed to confirm generalizability and clinical utility. (PsycInfo Database Record (c) 2026 APA, all rights reserved).