Neurodegenerative mechanisms of motor, executive, and memory decline in females with Fragile X-associated tremor/ataxia syndrome (FXTAS)

项目总结/摘要 脆性X相关震颤/共济失调综合征（FXTAS）是一种严重的、进行性的衰老障碍， X染色体上FMR 1基因的“突变前”扩增（55-200个CGG重复）。前突变 FXTAS携带者表现出运动和认知能力下降，导致独立性丧失， 生命和过早死亡。FXTAS在男性中的外显率（60岁时>50%）高于女性前突变 携带者（16-20%），这可能是研究主要集中在男性的主要原因。 因此，对女性FXTAS相关的关键表型和脑机制的了解， 严格限制。这些知识差距需要解决，因为A）FXTAS在以下方面具有高度损害性： 女性和通常临床上不同于男性，和B）结构脑和遗传协会与临床 FXTAS的结果因性别而异，这表明需要性别特异性生物标志物来了解 疾病途径，并支持靶向治疗的发展。在拟议的R21中， 我们对FXTAS女性患者的初步研究中涉及的运动、执行和记忆表型， 在FXTAS女性（FXTAS+）、年龄匹配的无症状女性前突变携带者（FXTAS-） 和年龄匹配的健康女性对照。基于任务的功能磁共振成像（fMRI）研究 运动、执行和记忆过程的功能性磁共振成像研究也被提出，这些研究代表了已知的第一个功能性磁共振成像研究。 专注于FXTAS在女性中的应用。我们还将测试大脑与行为的关系， 分子靶点，包括CGG重复长度、等位基因重复不稳定性（AGG中断）和激活 比率（活性X染色体上具有正常FMR 1等位基因的细胞的比率），这似乎是至关重要的 调节前突变等位基因对女性大脑衰老的影响。根据最近的研究显示， 在FXTAS和阿尔茨海默病重叠的分子和细胞病理，我们也将进行 ApoE和KLOTHO基因对下游运动风险的修饰作用的探索性分析 以及女性前突变携带者的认知障碍。这些研究是推进我们的 长期目标是阐明FXTAS在女性中的神经退行性机制， 可以建立特定的方法来跟踪疾病进展和改进靶向治疗。

PROJECT SUMMARY/ABSTRACT Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe, progressive disorder of aging caused by “premutation” expansions (55-200 CGG repeats) of the FMR1 gene on the X chromosome. Premutation carriers with FXTAS show motor and cognitive declines resulting in loss of independence, reduced quality of life, and premature death. FXTAS is more penetrant among male (>50% by age 60) than female premutation carriers (16-20%), which likely is the major reason studies have focused primarily, if not exclusively, on males. As a result, knowledge of key phenotypes and brain mechanisms associated with FXTAS in females is severely limited. These knowledge gaps need to be addressed because A) FXTAS is highly impairing in women and often clinically different than for men, and B) structural brain and genetic associations with clinical outcomes vary across sexes in FXTAS, suggesting that sex-specific biomarkers are needed to understand disease pathways and to support the development of targeted therapies. In the proposed R21, quantitative motor, executive, and memory phenotypes implicated in our preliminary work on females with FXTAS will be studied in females with FXTAS (FXTAS+), age-matched asymptomatic female premutation carriers (FXTAS-), and age-matched healthy female controls. Task-based functional magnetic resonance imaging (fMRI) studies of motor, executive, and memory processes also are proposed; these represent the first known fMRI studies focused solely on FXTAS in women. We also will test brain-behavior relationships with key genetic and molecular targets, including CGG repeat length, allele repeat instability (AGG interruptions), and activation ratio (ratio of cells with the normal FMR1 allele on the active X chromosome), which appears to critically modulate the impact of the premutation allele on brain aging in females. Based on recent studies showing overlapping molecular and cellular pathologies in FXTAS and Alzheimer's Disease, we also will conduct exploratory analyses of the modifying effects of the ApoE and KLOTHO genes on risk for downstream motor and cognitive impairments in female premutation carriers. These studies are the first step in advancing our long-term goal of clarifying neurodegenerative mechanisms of FXTAS in women so that more sensitive, sex- specific methods can be established to track disease progression and advance targeted therapeutics.