Cognitive Deficits in Spinocerebellar Ataxia Type 2: A Comparative Analysis of Pre-ataxic and Ataxic Stages.

Abstract

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder characterized by cerebellar motor symptoms. The extent and timing of cognitive involvement, particularly in pre-ataxic carriers, remain unclear. To assess cognitive performance across clinical stages of SCA2 and investigate early neurocognitive changes in pre-ataxic individuals. We evaluated 52 genetically confirmed participants from a rural Brazilian cohort: 16 pre-ataxic carriers, 12 symptomatic patients, and 24 intrafamilial controls. A standardized neuropsychological battery assessed global cognition, executive function, memory, visuospatial abilities, attention/working memory, mood, and language. Group comparisons and correlations were adjusted using False Discovery Rate (FDR) correction. Pre-ataxic carriers performed comparably to their intrafamilial controls across all cognitive domains, with no significant group differences except for the FAB total score, and showed no associations with estimated time to disease onset. Executive dysfunction emerged as the most prominent cognitive feature of manifest SCA2 and was more strongly associated with CAG repeat length than with clinical disease markers. In this genetically and environmentally homogeneous cohort, only limited measurable cognitive impairment was observed in pre-ataxic carriers. These findings underscore the importance of longitudinal and multimodal studies to elucidate the timing and underlying mechanisms of cognitive decline in SCA2.