Language as a Candidate Marker of FXTAS in FMR1 Premutation Carriers

语言作为 FMR1 预突变载体中 FXTAS 的候选标记

• 批准号: 10705826
• 负责人: Alexis Nell Maltman
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705826
• 关键词: Address; Adult; Affect; Age; Age Years; Age-associated memory impairment; Aging; Alzheimer' s Disease; Clinical; Cognitive; Data; Diagnosis; Disease; Disease Marker; Disease Progression; Executive Dysfunction; Exhibits; FMR1; FMR1 Premutation; FXTAS; Female; Functional disorder; Gait Ataxia; Genetic; Goals; Health; Impaired cognition; Individual; Intention Tremor; Interpersonal Relations; Knowledge; Language; Link; Literature; Measures; Mental Health; Mission; Names; National Institute on Deafness and Other Communication Disorders; Nature; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Nucleotides; Participant; Patient Self-Report; Personal Satisfaction; Phenotype; Prevalence; Production; Productivity; Public Health; Quality of life; Questionnaires; Research; Risk; Sampling; Semantics; Standardization; Strategic Planning; Subgroup; Testing; United States; United States National Institutes of Health; Variant; Woman; Work; X Chromosome; age related; age related neurodegeneration; aged; candidate identification; candidate marker; cerebral atrophy; comparison control; design; disability; executive function; genetic variant; healthy aging; high risk; language impairment; lexical; male; men; mutation carrier; physical conditioning; pre-clinical; recruit; sex; verbal; virtual

PROJECT ABSTRACT The FMR1 premutation (PM) affects ~1 in 150 women and ~1 in 470 men in the United States, and can have a significant effect on physical and mental health. Forty percent of males and 16% of female PM carriers are diagnosed with fragile X-associated tremor/ataxia syndrome (FXTAS) between 55-60 years of age, though who will manifest the disease is unknown. FXTAS is characterized by executive dysfunction, gait ataxia, and intention tremor. In the absence of clear markers of disease progression among PM carriers, it is essential to characterize language. Language predicts neurocognitive decline in related conditions (e.g., Alzheimer’s) 10-20 years prior to diagnosis. Language is a promising candidate marker of FXTAS as female PM carriers show age-related changes in pragmatics and lexical-semantics, which have been linked to executive dysfunction. Executive function and language difficulties may adversely impact quality of life. No studies to date have examined language among both male and female PM carriers, limiting our understanding of potential preclinical markers of FXTAS. As a first step, the proposed project will comprehensively examine language among PM carriers in comparison to healthy controls. Without such data, this severely limits our ability to (a) fully understand the impact of the FMR1 PM, (b) examine cognitive correlates implicated in FXTAS (i.e., executive dysfunction), and (c) understand the implications of language use and executive dysfunction on quality of life. This proposal addresses these limitations with three aims: 1) Examine pragmatic and lexical-semantic language among male and female PM carriers in comparison to healthy age- and sex- matched controls; 2) evaluate interactions of age and executive functioning on language; and 3) assess interactions between language and executive function on quality of life. This study will be completed virtually with a cross-sectional sample of 60 PM carriers (30 males, 30 females) without FXTAS and 40 healthy age- and sex-matched controls (20 males, 20 females) between the ages of 35-55. Participants from across the U.S. will be recruited. Participants will complete virtual language elicitation and executive function tasks, and self-report measures of executive function and quality of life. Results from this proposal are expected to inform the nature of language differences among PM carriers compared to controls. It is also expected that age and executive function will interact to adversely influence pragmatic and lexical-semantic language in PM carriers but not controls, which would implicate potential neurocognitive decline. Finally, we anticipate that poorer language and executive functions will adversely affect quality of life among PM carriers. This proposal is consistent with the mission of the National Institutes of Health to enhance health and reduce disability by expanding our understanding of a neurodegenerative condition associated with a common genetic variant, the FMR1 PM. It also contributes to the strategic mission of the National Institute on Deafness and Other Communication Disorders by informing knowledge on the basis of language impairments among individuals with neurodegenerative disorders and links with quality of life.

项目摘要 FMR1 Premuont（PM）在美国影响150名女性中的〜1，在470名男性中有〜1个，可以有一个 对身心健康的重大影响。 40％的男性和16％的女性PM携带者为 诊断患有X脆性X相关震颤/共济失调综合征（FXTA）在55-60岁之间，尽管谁是谁 将表现出疾病是未知的。 FXTA的特征是执行功能障碍，步态共济失调和意图 震颤。在没有PM载体之间疾病进展的明确标记的情况下，必须表征 语言。语言预测相关条件的神经认知能力下降（例如，阿尔茨海默氏症）10 - 20年 进行诊断。语言是FXTA的承诺候选标记，因为女性PM载体显示与年龄有关 与执行功能障碍相关的语用和词汇 - 仪式的变化。管理人员 功能和语言困难可能会对生活质量产生不利影响。迄今为止尚未研究 男性和女性PM载体的语言，限制了我们对潜在临床前标记的理解 fxtas。作为第一步，拟议的项目将在PM载体之间全面检查 与健康对照的比较。没有这样的数据，这严重限制了我们（a）完全理解影响的能力 在FMR1 PM中，（b）检查了在FXTA（即执行功能障碍）中实现的认知相关性，并且（c） 了解语言使用和执行功能障碍对生活质量的影响。该提案解决了 这些限制具有三个目的：1）检查男性和女性的务实和词汇语义语言 与健康年龄和性别匹配的对照相比，PM载体； 2）评估年龄相互作用和 在语言上执行执行； 3）语言和执行功能之间的评估互动 生活质量。这项研究实际上将通过60 pm携带者的横截面样本完成（30名男性， 30位女性）没有FXTA和40个健康年龄和性别匹配的对照（20名男性，20位女性） 年龄为35-55。来自美国各地的参与者将被招募。参与者将完成虚拟语言 启发和执行功能任务以及执行功能和生活质量的自我报告衡量标准。结果 与该提案相比 控件。还可以预期，年龄和执行功能将互动以不利影响务实和 PM载体中的词汇语义语言，但不能控制，这将暗示潜在的神经认知能力下降。 最后，我们预计语言和执行功能会对PM之间的生活质量产生不利影响 载体。该提案与美国国立卫生研究院的使命一致，以增强健康和 通过扩展我们对与常见的神经退行性疾病的理解来减少残疾 遗传变异，FMR1 PM。它还有助于国家聋哑研究所的战略使命 和其他沟通障碍，通过根据语言障碍为基础告知知识 具有神经退行性疾病的人，并与生活质量联系在一起。