Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

FMR1 前突变母携带者的衰老症状轨迹

• 批准号: 10712277
• 负责人: Jessica Klusek
• 金额: $ 39.55万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712277
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein Precursor; Biological; Child; Clinical Management; Cognitive; Consensus; DNA Sequence Alteration; Data; Dementia; Development; Diagnosis; Disease; FMR1; FMR1 Premutation; FXTAS; Failure; Family; Female; Fragile X Syndrome; Functional disorder; Future; Genes; Genetic; Genetic Variation; Genotype; Health; High Prevalence; Impaired cognition; Knowledge; Link; Mediating; Methods; Molecular Abnormality; Molecular Genetics; Mothers; Neurodegenerative Disorders; Neuropsychological Tests; Outcome; Paper; Parents; Participant; Pathogenesis; Pathologic Processes; Pathway interactions; Performance; Phenotype; Play; Population; Postdoctoral Fellow; Protein Biosynthesis; Regulation; Research; Resources; Risk; Role; Sampling; Sex Chromosomes; Symptoms; Tandem Repeat Sequences; Time; Woman; Work; age related; aged; career; clinical development; clinical effect; clinically significant; cognitive performance; dementia risk; genetic risk factor; genome wide association study; improved outcome; male; men; mild cognitive impairment; neuropathology; novel; preclinical study; repository; young mother

ABSTRACT Overview. The FXpm is a prevalent genetic abnormality caused by an expanded CGG sequence on the FMR1 gene1. The associated phenotype includes age-related cognitive decline2-11, elevated rates of dementia12, and risk for neurodegenerative disease13,14. Although the FXpm is about twice as prevalent in women than men (1:151 females vs 1:468 males1,15), current understanding of age-related clinical effects of the FXpm comes almost entirely from the study of men. Because FXpm women can pass the gene to their children which may cause fragile X syndrome, most extant research has focused on young mothers and their children, with few studies including FXpm women over the age of 60. Failure to characterize the age-related phenotype of FXpm in women is a major barrier to clinical management, as we lack the data needed to understand the age-related clinical effects of this genotype in women and develop treatments. Emerging evidence suggests that FXpm women may be at heightened risk for Alzheimer’s Disease (AD) and Related Dementias (ADRD). AD-type neuropathology has been observed in FXpm women at postmortem16-18 and FMR1 protein plays a known role in the pathogenesis of neurodegenerative disease, including in the regulation of amyloid precursor protein (APP)19-24. Evidence suggests that FXpm men have ~6-fold increased risk for dementia12. Yet, there has been no prior systematic study of ADRD in FXpm women. Our pilot data suggest that FXpm women are 13x more likely to score below cut-offs for mild cognitive impairment (MCI) on cognitive screeners than matched controls, underscoring the need to investigate ADRD risk in this group. Moreover, preliminary studies suggest that AD mechanisms may interact with FMR1 to increase vulnerability for disease in FXpm carriers. For example, FXpm carriers who have the APOE ε4 allele are at a 12-fold increased risk for developing Fragile X Associated Tremor Ataxia Syndrome, a late onset neurodegenerative disease caused by the FXpm25. However, no studies have examined APOE specifically in FXpm women or in relation to other FXpm phenotypic outcomes, such as impaired cognitive performance or ADRD. Supplement Aims. This proposal will extend our parent R01 focused on aging symptom trajectories in FXpm women (R01AG073374) to add new questions regarding ADRD risk. Specifically, we aim to characterize MCI cognitive phenotypes in FXpm women compared to matched women with MCI and health controls (Aim 1); describe the rates clinician consensus MCI diagnoses in FXpm women (Aim 2); and examine potential genetic risk factors (APOE ε4 and FMR1-related molecular genetic variation) in relation to impaired cognitive performance (Aim 3). We will accomplish these aims by adding a comprehensive neuropsychological test battery that has been well-established in ADRD research to the parent R01 (the NACC-UDS326). Leveraging available resources, methods, and data from existing repositories (ADNI, Co-I Joseph’s R01AG55132) we will compare the performance of FXpm women to matched women with MCI and healthy controls drawn from the archival repositories. We will also add new APOE genotyping and clinician consensus MCI diagnoses to our FXpm sample to inform genetic factors and the presentation of clinically significant cognitive impairment in FXpm women. This approach is highly feasible and will yield data on a well-powered participant sample of 75 FXpm carrier mothers, 140 matched MCI women, and 215 healthy control women, aged 45-80 years, to address our aims. Impact and Relevance to ADRD. This Supplement will represent the first attempt to characterize MCI cognitive phenotypes and AD genetic risk factors in FXpm women, addressing a critical knowledge gap. A direct link between FMR1 and AD is supported by a large body of research showing that FMR1 mediates APP synthesis, which is central to AD pathogenesis24,27. However, because FMR1 is reflected by a polymorphic tandem repeat located on a sex chromosome, it has not been included in existing large-scale ADRD genome- wide association studies28,29, leaving major knowledge gaps. A significant impact of this Supplement will be illuminating the role of FMR1 in ADRD risk. This pursuit is highly novel and will propel the field forward in understanding genetic mechanisms and associated biological pathways implicated in ADRD. Another significant impact will be describing, for the first time, ADRD risk in FXpm women as they age. These efforts have significant implications for the development of clinical management strategies to improve outcomes for both FXpm mothers and their children with fragile X syndrome. This Supplement has relevance to a large swath of the population given the high prevalence of the FXpm genotype (1:151 females, 1:468 males)1,15. Stimulating Future ADRD Research. This work will provide foundational new information on the overlap and divergence of cognitive phenotypes across FXpm and MCI, laying the groundwork for future mechanistic studies, such as those incorporating AD biomarkers or preclinical studies aimed at elucidating the mechanisms through which the FMR1 may interact with ADRD pathological processes. This work will inform the development of a larger R01 proposal and result in several papers and presentations on ADRD risk associated with FMR1 gene dysfunction. Moreover, the PI’s lab also includes a number of graduate and postdoctoral trainees who are pursuing research careers and will be introduced to ADRD through this work.

摘要 概述。FXPM是一种由FMR1上扩展的CGG序列引起的流行的遗传异常 基因1。相关的表型包括与年龄相关的认知功能下降2-11，痴呆率升高12，以及 神经退行性疾病的风险13，14.尽管FXPM在女性中的患病率大约是男性的两倍 (1：151女性对1：468男性1，15)，目前对FXPM与年龄相关的临床效应的理解如下 几乎完全来自对男性的研究。因为FXPM女性可以将基因传递给她们的孩子，这可能会 导致脆性X综合征，现有的大多数研究都集中在年轻母亲和她们的孩子身上，很少有 研究包括60岁以上的FXPM女性。未能确定FXPM的年龄相关表型 女性是临床管理的主要障碍，因为我们缺乏了解与年龄相关的 这种基因对女性的临床影响，并开发治疗方法。 新的证据表明，FXPM女性患阿尔茨海默病(AD)的风险可能更高 相关痴呆症(ADRD)。在死后16-18岁的FXPM妇女中观察到了AD型神经病理 FMR1蛋白在神经退行性疾病的发病机制中发挥着已知的作用，包括在 淀粉样前体蛋白(APP)19-24的调控有证据表明，FXPM男性的数量增加了约6倍 痴呆症风险12。然而，之前还没有对FXPM女性的ADRD进行系统研究。我们的试点数据 提示FXPM女性在轻度认知障碍(MCI)方面得分低于临界值的可能性是正常女性的13倍 认知筛查者高于匹配的对照组，强调了在这一群体中调查ADRD风险的必要性。 此外，初步研究表明，AD机制可能与FMR1相互作用，从而增加对 FXPM携带者中的疾病。例如，携带载脂蛋白Eε4等位基因的FXPM携带者的风险增加了12倍 罹患脆性X相关震颤共济失调综合征的风险，这是一种迟发的神经退行性疾病 由FXpm25引起。然而，没有研究专门研究apoe在FXPM妇女中或与 其他FXPM表型结果，如认知能力受损或ADRD。 补充目标。此建议将扩展我们的父代R01，重点放在FXPM中的老化症状轨迹上 妇女(R01AG073374)增加了关于ADRD风险的新问题。具体地说，我们的目标是描述MCI FXPM女性与匹配的MCI和健康对照组女性的认知表型比较(目标1)； 描述FXPM女性的临床医生共识MCI诊断率(目标2)；并检查潜在的基因 与认知损害相关的危险因素(载脂蛋白E、ε4和FMR1相关分子遗传变异) 业绩(目标3)。我们将通过增加一项全面的神经心理测试来实现这些目标 电池已经在ADRD研究中得到了很好的证实，以母公司R01(NACC-UDS326)为例。利用 来自现有存储库(ADNI，Co-I Joseph‘s R01AG55132)的可用资源、方法和数据 比较FXPM女性与匹配的MCI女性和健康对照组的表现 档案库。我们还将增加新的APOE基因分型和临床医生共识MCI诊断 FXPM样本告知遗传因素和FXPM中临床显著认知障碍的表现 女人。这种方法是高度可行的，并将在75FXPM的强大参与者样本上产生数据 携带者母亲，140名匹配的MCI妇女，以及215名年龄在45-80岁的健康对照妇女，来解决我们的 目标。 对ADRD的影响和相关性。本增刊将是对MCI的首次尝试 FXPM女性的认知表型和AD遗传风险因素，解决了一个关键的知识差距。一个 FMR1和AD之间的直接联系得到了大量研究的支持，这些研究表明FMR1介导APP 合成，这是阿尔茨海默病发病的中心24，27。但是，因为FMR1由 多态 串联重复序列位于性染色体上，尚未被现有的大规模ADRD所包含 基因组- 广泛的社团学习28，29，留下了重大的知识空白。本副刊的重大影响将是 阐明FMR1在ADRD风险中的作用。这一追求是非常新颖的，并将推动该领域在 了解ADRD所涉及的遗传机制和相关的生物途径。另一个 重大影响将首次描述FXPM妇女随着年龄的增长而发生ADRD的风险。这些努力 对制定临床管理策略以改善预后具有重要意义 FXPM母亲和她们的孩子都患有脆性X综合征。这份副刊对一位 鉴于FXPM基因的高流行率(1：151女性，1：468男性)1，15。 激励未来的ADRD研究。这项工作将提供关于重叠和 FXPM和MCI的认知表型差异，为未来的机械论奠定了基础 研究，如那些包含AD生物标记物的研究或旨在阐明机制的临床前研究 FMR1可能通过它与ADRD病理过程相互作用。这项工作将向 制定更大的R01提案，并就相关的ADRD风险发表多篇论文和演示文稿 有FMR1基因功能障碍。此外，PI的实验室还包括一些研究生和博士后 正在从事研究工作并将通过这项工作被介绍给ADRD的受训人员。