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: 10579486
• 负责人: Alexis Nell Maltman
• 金额: $ 19.44万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579486
• 关键词: Address; Adult; Affect; Age; Age-Years; Age-associated memory impairment; Aging; Alzheimer' s Disease; Brain; 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; Participant; Patient Self-Report; Personal Satisfaction; Phenotype; Plant Roots; 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 marker; design; disability; executive function; genetic variant; healthy aging; high risk; language impairment; lexical; male; men; physical conditioning; pre-clinical; recruit; sex; 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 在美国，FMR1前突变(PM)影响~1/150女性和~1/470男性，并可能具有 对身心健康有显著影响。40%的男性和16%的女性PM携带者 在55-60岁之间被诊断为脆性X相关震颤/共济失调综合征(FXTAS)，尽管世卫组织 会不会表现出这种疾病还不得而知。FXTAS的特征是执行功能障碍、步态共济失调和意图 震颤。在PM携带者中缺乏明确的疾病进展标志的情况下，有必要对 语言。语言预测10-20年前相关疾病(如阿尔茨海默氏症)的神经认知能力下降 去做诊断。语言是FXTAS的一个有希望的候选标记，女性PM携带者显示与年龄相关 语用学和词汇语义学的变化，这与执行功能障碍有关。执行人员 功能和语言障碍可能会对生活质量产生不利影响。到目前为止还没有检查过任何研究 男性和女性PM携带者的语言，限制了我们对潜在的临床前标志物的了解 FXTAS的成员。作为第一步，拟议的项目将全面审查PM承运人在#年的语言 与健康对照组进行比较。没有这样的数据，这严重限制了我们(A)充分了解影响的能力 在FMR1 PM中，(B)检查与FXTAS有关的认知相关性(即，执行功能障碍)，以及(C) 了解语言使用和执行功能障碍对生活质量的影响。这项提案涉及 这些局限有三个目的：1)考察男性和女性的语用和词汇语义语言 PM携带者与年龄和性别匹配的健康对照组的比较；2)评估年龄和性别的交互作用 语言的执行功能；以及3)评估语言和执行功能之间的交互作用 生活质量。这项研究将以60名PM携带者(30名男性， 30名女性)和40名年龄和性别匹配的健康对照组(20名男性，20名女性)。 年龄在35-55岁之间。参与者将从美国各地招募。参与者将完成虚拟语言 启发性和执行功能任务，以及执行功能和生活质量的自我报告测量。结果 从这项提案中，预计将告知PM运营商之间语言差异的性质 控制。还预计年龄和执行功能将相互作用，从而对务实和 PM携带者中的词汇-语义语言，而不是对照组，这可能意味着潜在的神经认知能力下降。 最后，我们预计较差的语言和执行功能将对首相的生活质量产生不利影响 承运人。这项建议符合美国国立卫生研究院提高卫生和医疗水平的使命。 通过扩大我们对与常见疾病相关的神经退行性疾病的理解来减少残疾 基因变异，FMR1 PM它还有助于国家聋人研究所的战略使命 和其他沟通障碍，通过在语言障碍的基础上告知知识 患有神经退行性疾病并与生活质量有关的个人。