Background:
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder linked to a premutation (55-200 CGG repeats) in the FMR1 gene. Executive dysfunction, often appearing before motor symptoms, is an early indicator in male carriers. Previous studies have associated MRI findings, such as "Middle Cerebellar Peduncle" (MCP) signs and periventricular hyperintensities, with executive deficits in FXTAS (Hessl et al., 2023; Wang et al., 2022). This study investigates the relationship between BDS-2 scores and MRI findings in FXTAS individuals.

Methods:
Eighty-four FXTAS participants (ages 44-85) were enrolled in a genotype-phenotype study. The BDS-2 scale measured executive function, and FXTAS stages were assigned from 1 (mild/subclinical) to 5 (bedridden) (Bacalman et al., 2006). MRI scans were evaluated for atrophy, hyperintensities, and corpus callosum thinning (Hall et al., 2017).

Results:
BDS-2 scores significantly differed across FXTAS stages, with a strong inverse correlation, indicating neuropsychological decline worsens with disease progression. A Kruskal-Wallis test revealed significant differences in BDS-2 scores by FXTAS stage (p = 0.0009). Spearman’s correlation showed a strong inverse relationship between BDS-2 scores and FXTAS stages (ρ = -0.4, p < 0.0001), and moderate inverse correlations between BDS-2 scores and MRI findings in males (ρ = -0.55, p < 0.0001) and females (ρ = -0.40, p = 0.01).

Specific brain regions were analyzed: In females, higher Splenium (CC)-WM hyperintensity correlated with more cognitive decline. In males, MCP WM hyperintensity and cerebellar atrophy showed strong correlations with lower BDS-2 scores, with cerebellar atrophy showing the strongest association. Reduced cerebellar volume in males with FXTAS supports earlier findings of cerebellar thinning in this population. MRI markers like Splenium and MCP WM hyperintensities, and cerebellar volume are potential tools for tracking FXTAS progression.

Conclusion:
Neuropsychological decline, as measured by BDS-2 scores, correlates with FXTAS progression and MRI markers, particularly in males. The inverse relationships between BDS-2 scores and MRI findings—such as MCP WM hyperintensity and cerebellar atrophy in males, and Splenium (CC)-WM hyperintensity in females—suggest these structural changes may serve as biomarkers for FXTAS. These results highlight the utility of MRI markers in diagnosing and monitoring FXTAS progression.