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

女性脆性 X 相关震颤/共济失调综合征 (FXTAS) 运动、执行和记忆衰退的神经退行性机制

• 批准号: 10605693
• 负责人: MATTHEW W MOSCONI
• 金额: $ 27.12万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605693
• 关键词: Address; Age; Aging; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Apolipoprotein E; Autopsy; Behavior; Behavioral; Brain; CGG repeat; Case Study; Cells; Cerebellum; Cessation of life; Clinical; Clinical Research; Cognitive; Corpus striatum structure; Data; Dementia; Development; Dimensions; Disease; Disease Pathway; Disease Progression; Executive Dysfunction; FMR1; FMR1 Premutation; FXTAS; Female; Functional Magnetic Resonance Imaging; Genes; Genetic; Goals; Hippocampus; Impaired cognition; Impairment; Interruption; Knowledge; Length; Literature; Lobule; Memory; Memory Loss; Memory impairment; Methods; Middle frontal gyrus structure; Molecular; Molecular Profiling; Molecular Target; Motor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Oxidative Stress; Parahippocampal Gyrus; Parietal Lobe; Pathology; Pathway interactions; Patients; Pattern; Penetrance; Phenotype; Process; Quality of life; Retrieval; Risk; Saccades; Severity of illness; Symptoms; Testing; Woman; Work; X Chromosome; aging brain; behavior test; brain behavior; cellular pathology; cognitive change; genetic association; healthy aging; imaging study; infancy; male; memory process; men; mitochondrial dysfunction; molecular marker; molecular pathology; motor behavior; motor disorder; motor impairment; mutation carrier; neural; neurophysiology; oculomotor; premature; sex; specific biomarkers; targeted treatment; trait; verbal; visual information

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.

项目概要/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衰老疾病，由以下因素引起： X 染色体上 FMR1 基因的“前突变”扩展（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、生活质量下降 生命，以及过早的死亡。 FXTAS 在男性（60 岁以上 50%）中的渗透率高于女性前突变 携带者（16-20%），这可能是研究主要（如果不是全部）关注男性的主要原因。 因此，对女性 FXTAS 相关关键表型和大脑机制的了解 受到严格限制。这些知识差距需要解决，因为 A) FXTAS 严重损害了 女性的临床表现通常与男性不同，B) 大脑结构和遗传与临床的关联 FXTAS 中的结果因性别而异，这表明需要性别特异性生物标志物来理解 疾病途径并支持靶向治疗的开发。在拟议的 R21 中，定量 我们对患有 FXTAS 的女性进行的初步研究中涉及的运动、执行和记忆表型将是 在患有 FXTAS (FXTAS+) 的女性、年龄匹配的无症状女性前突变携带者 (FXTAS-) 中进行研究， 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 还提出了运动、执行和记忆过程的机制；这些代表了第一个已知的功能磁共振成像研究 仅专注于女性 FXTAS。我们还将测试大脑行为与关键遗传和行为的关系。 分子靶标，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 FMR1 等位基因的细胞的比率），这似乎对 调节前突变等位基因对女性大脑衰老的影响。根据最近的研究表明 FXTAS 和阿尔茨海默病的重叠分子和细胞病理学，我们还将进行 ApoE 和 KLOTHO 基因对下游运动风险的修饰作用的探索性分析 和女性前突变携带者的认知障碍。这些研究是推进我们的研究的第一步 长期目标是阐明女性 FXTAS 的神经退行性机制，以便对性更加敏感 可以建立具体方法来跟踪疾病进展并推进靶向治疗。