Intra-individual Variability in Prodromal Huntington Disease and Its Relationship to Genetic Burden

Area of Science:

• Neuroscience
• Cognitive Psychology
• Genetics

Background:

• Huntington disease (HD) is a neurodegenerative disorder with a prodromal phase characterized by subtle cognitive changes.
• Intra-individual variability (IIV), reflecting fluctuations in performance, is increasingly recognized as a potential indicator of cognitive dysfunction.

Purpose of the Study:

• To investigate the utility of across-task and within-task IIV in differentiating individuals in the prodromal stage of HD from healthy controls.
• To compare the sensitivity of different IIV measures in detecting cognitive changes associated with proximity to HD diagnosis.

Main Methods:

• The study analyzed data from 693 gene-expanded (prodromal HD) and 191 nongene-expanded (control) participants in the PREDICT-HD study.
• Intra-individual variability was assessed across 15 neuropsychological tasks and within a self-paced timing task.
• Cognitive processing speed was measured using the Symbol Digit Modalities Test (SDMT).

Main Results:

• Individuals closest to an HD diagnosis exhibited significantly higher across-task and within-task IIV compared to controls and those further from diagnosis.
• Effect sizes were larger for within-task variability measures (paced timing, paced tapping CV) and SDMT compared to across-task variability measures (CV, SD).
• Within-task variability measures demonstrated greater sensitivity in detecting cognitive alterations in prodromal HD participants near diagnosis.

Conclusions:

• Across-task variability may serve as a sensitive marker for cognitive decline in prodromal HD individuals approaching disease onset.
• Individual neuropsychological tasks, particularly those measuring within-task variability, yielded larger effect sizes than a composite across-task IIV index.
• These findings highlight the potential of IIV measures for early detection and monitoring of cognitive changes in Huntington disease.