Famula Jessica, Ferrer Emilio, Hagerman Randi J, Tassone Flora, Schneider Andrea, Rivera Susan M, Hessl David
MIND Institute, University of California Davis Health, 2825 50th Street, Sacramento, CA, 95817, USA.
Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.
J Neurodev Disord. 2022 Mar 23;14(1):23. doi: 10.1186/s11689-022-09436-y.
Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention.
This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm "converters," 15 Pm "nonconverters," 15 Nc) that were one-one matched on age, education, and socioeconomic status.
Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters.
Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.
FMR1前突变携带者患迟发性进行性神经退行性疾病——脆性X相关震颤/共济失调综合征（FXTAS）的风险增加，其特征为意向性震颤、步态共济失调和认知衰退。迄今为止的横断面研究已提供证据表明，神经心理学变化，如执行功能改变或细微的运动变化，可能先于正式的FXTAS发病，这可能是前驱状态的特征。然而，缺乏纵向数据阻碍了该领域对个体随时间推移的进展形成清晰的认识，而且我们对于风险的早期标志物以及可用于追踪干预反应的措施尚未达成共识。
这是一项纵向研究，纳入了64名在研究开始时无FXTAS的男性FMR1前突变携带者（Pm）和30名正常对照（Nc），年龄在40至80岁之间（Pm平均年龄M = 60.0岁；Nc平均年龄M = 57.4岁）。平均2.33年后，对50名Pm和22名Nc进行了重新评估，平均再过2.15年后，对37名Pm和20名Nc进行了第三次重新评估。在该研究期间，64名携带者中有18名（28%）转变为FXTAS。每个时间点的神经心理学评估，包括剑桥神经心理学测试自动成套测验（CANTAB）的各个部分，涉及情景记忆和工作记忆、抑制控制、视觉注意力、计划、运动的执行控制以及手部速度和灵活性等领域。基于年龄的混合模型用于检验全样本中各结局随时间变化的组间差异，并在15个三人组（n = 45；15名Pm“转变者”、15名Pm“未转变者”、15名Nc）中进一步评估差异，这些三人组在年龄、教育程度和社会经济地位上进行了一对一匹配。
与Nc相比，Pm在视觉工作记忆、运动灵活性、抑制控制和手部运动速度方面随时间的变化率显著更高。经过多重比较校正后，运动灵活性仍有显著效应。抑制控制能力恶化和手部运动变慢与FXTAS阶段的进展相关，但在进行多重比较校正后，这些效应在统计学上变得不显著。较高的FMR1 mRNA与手部反应时间变差相关，但经过多重比较后不显著，且没有其他分子指标与神经心理学变化相关。最后，三人组比较显示，与Pm未转变者相比，Pm转变者在计划和手部运动速度方面的下降速率更大。
执行功能的加速衰退和细微的运动变化，可能由额小脑回路介导，可能先于正式的FXTAS症状出现，然后随着症状出现而变化。需要进一步开展研究，以开发并统一各中心对FMR1携带者的临床评估，为该疾病未来的预防性和治疗性试验做好准备。
