medRxiv : the preprint server for health sciences · 2026
Utilizing Intraindividual Cognitive Variability to Predict Early Neuronal Synuclein Disease Progression.
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Combs Hannah L, Kurth Ryan, Nair Anuprita, York Michele K, Weintraub Daniel, Lafontant David-Erick, Caspell-Garcia Chelsea, Parkinson’s Progression Markers Initiative
Аннотация
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 (p = .003). Higher IIV-D was associated with worse motor symptoms, non-motor 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 one year (OR = 1.44, p = .008), controlling for baseline motor severity.
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.
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 (p = .003). Higher IIV-D was associated with worse motor symptoms, non-motor 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 one year (OR = 1.44, p = .008), controlling for baseline motor severity.
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.