Objective: To investigate the use of  the neuropsychological BDS-2 measures and its correlation with MRI findings and FXTAS stages[1]

Background: Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a single-gene progressive neurodegenerative condition that affects FMR1 (Fragile X Messenger Ribonucleoprotein-1)  premutation carriers. Executive dysfunction in male carriers precedes the development of the motor manifestations in FXTAS [2]. MRI findings including the “Middle Cerebellar Peduncle” sign combined with pallidal T2- weighted hyperintensities are associated with executive dysfunction in premutation carriers [3]

Method: 84 participants aged 44-85 years (mean 68.2±7.8 years) with FXTAS have been recruited as part of the longitudinal genotype-phenotype 4 (GP4) study. Participants were predominantly Caucasian (94%) and male (60%). Neuropsychological testing was performed at baseline using the 9 item BDS-2 scale with individual items scored between 0-3 and total score range between 0-27. MRI scoring criteria at baseline were used for cerebral/cerebellar atrophy, cerebral/cerebellar/middle cerebellar peduncle/pons/sub-insular/periventricular/splenium/genu white matter hyperintensity, and corpus callosum thickening with score of 0 = none, 1 = mild, 2 = moderate, 3 = severe [4].

Results: At baseline, significant differences in BDS-2 scores across FXTAS stages (Kruskal-Wallis p = 0.0009) were observed. Correlation analysis showed a strong inverse correlation between BDS-2 scores and FXTAS stages (Spearman’s ρ = -0.4,  p <0.0001).  Similarly, correlation analysis for BDS-2 total scores and total MRI scores for males (n=50) and females (n=35) groups showing a statistically significant inverse relationship, although the strength of the correlation is moderate (Spearman’s ρ  -0.55, p<0.0001 in males, and  ρ -0.40, p = 0.01 in females).

Conclusion: The BDS-2 demonstrates potential as a neuropsychological tool for tracking disease progression in individuals with FXTAS, complementing the use of MRI. Incorporating BDS-2 scores as an outcome measure in future clinical trials targeting the slowing of disease progression could significantly enhance the effectiveness in evaluating therapeutic interventions.

References: [1] S. Bacalman et al., “Psychiatric Phenotype of the Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) in Males,” J Clin Psychiatry, vol. 67, no. 01, pp. 87–94, Jan. 2006, doi: 10.4088/JCP.v67n0112.
[2] D. Hessl et al., “FMR1 Carriers Report Executive Function Changes Prior to Fragile X‐Associated Tremor/Ataxia Syndrome : A Longitudinal Study,” Movement Disorders, Dec. 2023, doi: 10.1002/mds.29695.
[3] J. Y. Wang et al., “Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation,” Front Neurol, vol. 13, Feb. 2022, doi: 10.3389/fneur.2022.797649.
[4] D. A. Hall et al., “The Corpus Callosum Splenium Sign in Fragile X‐Associated Tremor Ataxia Syndrome,” Mov Disord Clin Pract, vol. 4, no. 3, pp. 383–388, May 2017, doi: 10.1002/mdc3.12449.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/monitoring-progress-use-of-the-behavioral-dyscontrol-scale-2-bds-2-in-fxtas-fragile-x-associated-tremor-ataxia-syndrome-progression/