Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers

脆性 X 前突变携带者神经变性的轨迹和标志物

基本信息

批准号：
9249369
负责人：
DAVID R HESSL
金额：
$ 14.95万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249369
关键词：
Adult Affect Age Aging Alleles Amygdaloid structure Anxiety Anxiety Disorders Attention Autonomic Dysfunction Brain Brain Stem Clinical Research Data Dementia Deterioration Diffusion Magnetic Resonance Imaging Disease Disease Progression Early Intervention Emotions Enrollment Equilibrium Executive Dysfunction Exhibits FMR1 FXTAS Fiber Fragile X Premutation Fragile X Syndrome Functional Magnetic Resonance Imaging Functional disorder Future Gait Ataxia Genetic Hand Health Hippocampus (Brain)Impairment Individual Intention Tremor Intervention Length Life Limbic System Longitudinal Studies Measures Mediating Mental Depression Mental disorders Messenger RNA Molecular Molecular Genetics Mood Disorders Motor Nerve Degeneration Neurodegenerative Disorders Neurologic Neurologic Symptoms Neurons Nuclear Inclusion Onset of illness Parietal Parkinsonian Disorders Patients Penetrance Peripheral Nervous System Diseases Play Prevention Preventive care Preventive treatment Process Recording of previous events Research Risk Risk Factors Role Short-Term Memory Structure Symptoms Ventricular White Matter Disease White Matter Hyperintensity Work age related anxiety symptoms cerebral atrophy cognitive control cohort executive function flexibility frontal lobe frontal lobe function gain of function longitudinal design male memory recall men men&apos s group mild cognitive impairment mood symptom motor control nervous system disorder neuropsychiatric symptom neuropsychological programs prospective psychological symptom rate of change response social white matter

项目摘要

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.

描述（由申请人提供）：脆性 X (FMR1) 前突变携带者已被证明表现出轻度认知障碍和精神问题风险增加。此外，他们有患神经退行性疾病、脆性X相关震颤共济失调综合征（FXTAS）的风险，其特征是进行性步态共济失调、意向性震颤、帕金森症、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、白质疾病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 FMR1 mRNA 的毒性功能获得。该疾病的外显率存在差异且与年龄相关，到 80 岁时，75% 的男性前突变携带者受到影响。虽然 FXTAS 的特征已得到充分描述，但尚不清楚为什么一些携带者会受到影响而另一些携带者不会受到影响，并且对不同的进展速度和与疾病发作相关的危险因素知之甚少。在这个研究项目（“脆性 X 前突变携带者的边缘系统功能”）的前 5 年中，连同我们中心的其他合作研究，我们已经证明 FMR1 mRNA 的异常升高与海马体、杏仁核、和额叶功能，而这又与有 FXTAS 风险的男性前突变携带者的心理症状和社交缺陷、记忆力受损和工作记忆相关。我们的其他研究表明，与具有正常 FMR1 等位基因的对照相比，未 FXTAS 的成年携带者的大脑白质随着年龄的增长而恶化、脑干减少、心室容积增加，并且情绪和焦虑障碍的发生率较高。这项工作提供了有关疾病进展的潜在遗传、大脑和神经心理学风险因素的重要线索，但尚未完成前瞻性纵向研究来提供识别 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，检查 40 至 69 岁之间 FMR1 前突变的成年男性携带者的关键神经心理学和神经学因素的轨迹。我们将研究几种 FMR1 分子测量如何在调节这些关键因素的进展速度中发挥作用。该研究的结果将提供有关神经退行性变早期标志物的关键信息，当这些干预措施可用时，这将有助于识别最需要预防性护理和治疗的患者，并且可能确定跟踪未来干预措施反应的重要措施。