Emilio Ferrer

Background Men with fragile X‐associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross‐sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. Objective To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. Methods This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well‐matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty‐four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function‐Adult Version (BRIEF‐A) was completed by participants and their spouses/partners at each visit. Results Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self‐initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self‐report executive function problems at baseline significantly predicted later development of FXTAS. Conclusions Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.