Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers

描述（由申请人提供）：脆性X（FMR 1）前突变的携带者已被证明表现出轻度认知障碍和精神问题的风险增加。此外，他们有发生神经退行性疾病的风险，脆性X相关震颤共济失调综合征（FXTAS），其特征在于进行性步态共济失调、意向性震颤、帕金森综合征、痴呆、自主神经功能障碍和周围神经病变的神经学表现。FXTAS的神经病理学特征包括全脑萎缩、脑室扩大、白色病变以及神经元和星形细胞核内包涵体形成，神经精神症状包括抑郁、焦虑和执行功能障碍。FXTAS的假设分子遗传致病机制是FMR 1 mRNA的毒性功能获得性。这种疾病有一个可变的和与年龄相关的发病率，影响75%的男性前突变携带者的第八个十年的生活。虽然FXTAS的特征已经得到了很好的描述，但尚不清楚为什么有些携带者会受到影响，而另一些则不会，并且与疾病发作相关的可变进展率和风险因素也知之甚少。在这项研究计划的前5年里，（“脆性X前突变携带者的边缘系统功能”），以及我们中心的其他合作研究，我们已经证明FMR 1 mRNA的异常升高与海马体，杏仁核和额叶功能降低有关，而这些功能又与心理症状和社会缺陷相关，有FXTAS风险的男性前突变携带者的记忆回忆和工作记忆受损。我们的其他研究显示，与FMR 1等位基因正常的对照组相比，无FXTAS的成年携带者的大脑白色物质随年龄增长而退化，脑干减少，心室容积增加，情绪和焦虑障碍的发生率较高。这项工作为疾病进展的潜在遗传、大脑和神经心理学风险因素提供了重要线索，但尚未完成前瞻性纵向研究，提供确定FXTAS风险或保护因素所需的关键数据。在当前的项目中，我们将使用纵向设计，与没有前突变的男性对照相比，研究40至69岁之间FMR 1前突变成年男性携带者的关键神经心理学和神经学因素的轨迹。我们将研究几个FMR 1分子措施如何在介导这些关键因素的进展速度中发挥作用。这项研究的结果将提供有关神经退行性疾病早期标志物的关键信息，这些信息将有助于识别最需要预防性护理和治疗的患者，因为这些干预措施变得可用，并且它可能会确定重要的措施来跟踪未来对干预措施的反应。

DESCRIPTION (provided by applicant): Carriers of the fragile X (FMR1) premutation have been shown to exhibit mild cognitive impairments and increased risk for psychiatric problems. Furthermore, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor ataxia syndrome (FXTAS), characterized by neurological manifestations of progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, and peripheral neuropathy. Neuropathological features of FXTAS include whole brain atrophy, ventricular enlargement, white matter disease, and neuronal and astrocytic intranuclear inclusion formation and neuropsychiatric symptoms include depression, anxiety, and executive dysfunction. The hypothesized molecular genetic pathogenic mechanism of FXTAS is toxic gain-of-function of FMR1 mRNA. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. While the features of FXTAS have been well-described, it is not known why some carriers become affected and others do not, and the variable rate of progression and risk factors associated with disease onset are poorly understood. In the first 5 years of this program of research ("Limbic System Function in Carriers of the Fragile X Premutation"), alongside other collaborative studies at our center, we have demonstrated that abnormal elevation of FMR1 mRNA is associated with reduced hippocampus, amygdala, and frontal lobe function, which in turn are correlated with psychological symptoms and social deficits, impaired memory recall and working memory in male premutation carriers at risk for FXTAS. Our other studies have shown brain white matter deterioration with age, reduced brain stem and increased ventricular volume, and high rates of mood and anxiety disorders in adult carriers without FXTAS compared to controls with normal FMR1 alleles. This work has provided important clues about potential genetic, brain and neuropsychological risk factors for disease progression, however no prospective longitudinal studies have been completed that provide critical data required to identify risk or protective factors for FXTAS. For the current project, we will examine the trajectory of key neuropsychological and neurological factors in adult male carriers of the FMR1 premutation between the ages of 40 and 69, in comparison to male controls without the premutation, using a longitudinal design. We will examine how several FMR1 molecular measures play a role in mediating the rate of progression of these key factors. The results of the study will provide critical information about the early markers of neurodegeneration that will aid in identification o patients most in need of preventive care and treatment as these interventions become available, and it may identify important measures to track response to interventions in the future.