Utilizing Intraindividual Cognitive Variability to Predict Early Neuronal Synuclein Disease Progression

Area of Science:

• Neuroscience
• Cognitive Science
• Neurology

Background:

• Neuronal synuclein disease (NSD) is characterized by alpha-synuclein pathology and often dopaminergic dysfunction.
• Prodromal NSD stages (2A and 2B) show subtle clinical signs without functional impairment.
• Intraindividual variability/dispersion (IIV-D) across cognitive tasks is a potential early marker for neurodegeneration.

Purpose of the Study:

• To determine if IIV-D distinguishes NSD Stage 2 participants from healthy controls.
• To assess if IIV-D predicts progression to later NSD stages.

Main Methods:

• Analysis of 934 participants (832 Stage 2 NSD, 102 controls) from the Parkinson's Progression Markers Initiative.
• Quantification of IIV-D using total coefficient of variation (CoV) and attention/executive CoV across 11 neuropsychological tests.
• Group comparisons and logistic regression to evaluate associations between IIV-D, clinical factors, and disease progression.

Main Results:

• Stage 2 participants showed significantly higher CoV than controls (p = .003).
• Elevated IIV-D correlated with worse motor symptoms, non-motor burden, and functional impairment.
• Higher baseline CoV predicted conversion to Stage 3+ NSD within one year (OR = 1.44, p = .008), independent of motor severity.

Conclusions:

• IIV-D, particularly CoV, serves as a sensitive cognitive marker for early NSD.
• Cognitive dispersion metrics can predict short-term disease progression in NSD.
• Integrating IIV-D into early detection strategies for prodromal synucleinopathies is recommended, pending further validation.