Introduction

Premutation carriers of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease characterized by motor, cognitive, and psychiatric decline as well as cerebellar and cerebral white matter pathology. Several studies have documented preclinical sensorimotor issues in aging premutation carriers, but the extent to which sensorimotor brain systems are affected and may represent early indicators of atypical neurodegeneration has not been determined.

Materials and methods

Eighteen healthy controls and 16 FMR1 premutation carriers (including five with possible, probable, or definite FXTAS) group-matched on age, sex, and handedness completed a visually guided precision gripping task with their right hand during fMRI. During the test, they used a modified pinch grip to press at 60% of their maximum force against a custom fiber-optic transducer. Participants viewed a horizontal white force bar that moved upward with increased force and downward with decreased force and a static target bar that was red during rest and turned green to cue the participant to begin pressing at the beginning of each trial. Participants were instructed to press so that the white force bar stayed as steady as possible at the level of the green target bar. Trials were 2-sec in duration and alternated with 2-sec rest periods. Five 24-sec blocks consisting of six trials were presented. Participants’ reaction time, the accuracy of their force relative to the target force, and the variability of their force accuracy across trials were examined. BOLD signal change and task-based functional connectivity (FC) were examined during force vs. rest.

Results

Relative to healthy controls, premutation carriers showed increased trial-to-trial variability of force output, though this was specific to younger premutation carriers in our sample. Relative to healthy controls, premutation carriers also showed reduced extrastriate activation during force relative to rest. FC between ipsilateral cerebellar Crus I and extrastriate cortex was reduced in premutation carriers compared to controls. Reduced Crus I-extrastriate FC was related to increased force accuracy variability in premutation carriers. Increased reaction time was associated with more severe clinically rated neurological abnormalities.

Conclusions

Findings of reduced activation in extrastriate cortex and reduced Crus I-extrastriate FC implicate deficient visual feedback processing and reduced cerebellar modulation of corrective motor commands. Our results are consistent with documented cerebellar pathology and visual-spatial processing in FXTAS and pre-symptomatic premutation carriers, and suggest FC alterations of cerebellar-cortical networks during sensorimotor behavior may represent a “prodromal” feature associated with FXTAS degeneration.

中文翻译：

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在衰老的FMR1基因预突变载体的感觉运动行为过程中，小脑皮质功能和连接性。

介绍

FMR1基因的突变前携带者有发展为脆弱的X相关震颤/共济失调综合征（FXTAS）的风险，FXTAS是一种以运动，认知和精神病性衰退以及小脑和脑白质病变为特征的神经退行性疾病。几项研究已记录了老化的突变前携带者中的临床前感觉运动问题，但尚未确定感觉运动脑系统受到影响的程度，并可能代表非典型神经变性的早期指标。

材料和方法

18个健康对照组和16个FMR1在年龄，性别和惯性方面进行分组匹配的预变异携带者（包括五种可能的，可能的或确定的FXTAS）在fMRI期间用右手完成了视觉引导的精确抓握任务。在测试过程中，他们使用了改良的压紧握把，以最大力的60％压向定制的光纤传感器。参与者观察到水平的白色力条随着力的增加而向上移动，并随着力的减小而向下运动；静止的目标条在休息时变为红色，并变为绿色以提示参与者在每次试验开始时就开始按压。指示参与者按使白色力条尽可能稳定地保持在绿色目标条的水平。试验持续时间为2秒，休息时间为2秒。提出了由六个试验组成的五个24秒块。研究对象的反应时间，他们的力量相对于目标力量的准确性以及他们的力量准确性在整个试验中的变异性。在强制与休息期间检查了大胆的信号变化和基于任务的功能连接性（FC）。

结果

相对于健康对照，变异前携带者显示出力输出的试验间变化，尽管这是我们样本中年轻的变异前携带者所特有的。相对于健康的对照，突变前的携带者在受力时也表现出相对于静止状态减少的外泌体激活。与对照相比，在突变前携带者中，同侧小脑Crus I和足外皮层之间的FC减少。降低的Crus I-残基FC与预突变载体中力准确度变异性增加有关。反应时间增加与临床上更为严重的神经系统异常有关。

结论

研究发现，外泌皮层的激活减少，而Crus I-祖母FC减少，这意味着视觉反馈处理不足，纠正运动命令的小脑调制降低。我们的结果与FXTAS和有症状的预突变携带者中小脑病理学和视觉空间处理的记录相一致，并表明在感觉运动行为期间小脑皮质网络的FC改变可能代表与FXTAS变性相关的“前驱性”特征。