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

基本信息

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
项目类别：
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&apos 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

项目摘要

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) 影响大约每 150 名女性中的 1 名和大约每 470 名男性中的 1 名，并且可能会导致 40% 的男性和 16% 的女性 PM 携带者有显着影响。 55-60 岁之间被诊断患有脆性 X 相关震颤/共济失调综合征 (FXTAS)，但 FXTAS 的表现尚不清楚，其特征是执行功能障碍、步态共济失调和意向。在缺乏 PM 携带者疾病进展的明确标志的情况下，有必要确定其特征。语言可以预测 10-20 年前相关疾病（例如阿尔茨海默病）的神经认知能力下降。语言是 FXTAS 的一个有前途的候选标志物，因为女性 PM 携带者表现出与年龄相关的特征。语用学和词汇语义学的变化与执行功能障碍有关。迄今为止还没有研究表明功能和语言困难可能会对生活质量产生不利影响。男性和女性 PM 携带者之间的语言，限制了我们对潜在临床前标志物的理解作为第一步，拟议项目将全面检查 PM 运营商之间的语言。与健康对照相比，如果没有这些数据，这将严重限制我们 (a) 充分了解其影响的能力。 FMR1 PM 的分析，(b) 检查 FXTAS 中涉及的认知相关性（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。这些限制有三个目的：1）检查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相比；2) 评估年龄和性别的相互作用；语言的执行功能；3）评估语言和执行功能之间的相互作用这项研究将以 60 名 PM 携带者（30 名男性， 30 名女性）没有 FXTAS 和 40 名年龄和性别匹配的健康对照（20 名男性，20 名女性）来自美国各地的参与者将被招募，年龄在 35-55 岁之间。启发和执行功能任务，以及执行功能和生活质量结果的自我报告测量。预计该提案将揭示 PM 运营商之间语言差异的本质预计年龄和执行功能也会相互作用，对务实和执行能力产生不利影响。 PM 携带者的词汇语义语言，但对照组则不然，这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 PM 的生活质量产生不利影响该提案符合美国国立卫生研究院促进健康和健康的使命。通过扩大我们对与常见疾病相关的神经退行性疾病的了解来减少残疾遗传变异，FMR1 PM 它也有助于国家耳聋研究所的战略使命。和其他沟通障碍，通过根据语言障碍告知知识患有神经退行性疾病的个体并与生活质量相关。