Motor Function in Older Adults: the Importance of Apolipoprotein-E ??4 Inheritanc

老年人的运动功能：载脂蛋白-E ??4 遗传的重要性

• 批准号: 8690518
• 负责人: SANDRA K HUNTER
• 金额: $ 22.68万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690518
• 关键词: Acute; Adopted; Adult; Age; Aging; Alleles; Alzheimer' s disease risk; Apolipoprotein E; Area; Attention; Biological Neural Networks; Brain; Clinical; Cognitive; Data; Dual-Energy X-Ray Absorptiometry; Effectiveness; Elderly; Electric Stimulation; Equilibrium; Exercise; Fatigue; Financial cost; Functional disorder; Future; Genes; Genetic; Glutamate Receptor; Glutamates; Human; Impairment; Intervention; Life; Limb structure; Lower Extremity; Masks; Mediating; Motor; Motor Cortex; Muscle; Muscle Weakness; Muscle function; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve; Neurons; Performance; Physical activity; Physiologic pulse; Population; Property; Protocols documentation; Risk; Rodent; Role; Sex Characteristics; Societies; Speed; Stimulus; Synapses; Testing; Time; Transcranial magnetic stimulation; Walking; Woman; Work; age related; apolipoprotein E-4; cost; ergonomics; functional decline; genetic variant; in vivo; innovation; insight; men; motor impairment; muscle form; neural facilitation; neuromechanism; older men; older women; performance tests; prevent; public health relevance; receptor function; relating to nervous system; sex; young adult

DESCRIPTION (provided by applicant): Increased age-related variability of motor function indicates that some older adults are more vulnerable to motor decline than others. Impaired motor function in vulnerable adults, leads to loss of ability to work and to lost independence, ultimately leading to substantially greater costs to an aging society. This proposal adopts a new and innovative approach to understanding motor function and motor fatigue (exercise induced reduction in strength) in vulnerable older men and women. We explore the large inter-subject variability that occurs with increased age to provide insight to a genetic mechanism underlying motor decline of the lower limb in men and women. Specifically, we associate inter-subject variability of motor function and fatigue with inheritance of the ¿4 allele of the apolipoprotein-E (APOE) gene. We propose that APOE ¿4 carriers have reduced effectiveness of the glutamate receptor (NMDA) in motor cortical areas and a subsequent reduction in intracortical excitability and lower neural drive during motor tasks than APOE ¿4 non carriers: these mechanisms will be assessed with transcranial magnetic stimulation (TMS). Despite the substantive potential for intervention with vulnerable older adults, the cortical mechanisms underlying motor decline have received very limited attention. APOE ¿4 inheritance is typically associated with risk of Alzheimer's Disease but was recently shown to increase the risk of motor function decline with advanced age. Whether motor fatigue during dynamic tasks, which is a common component of ergonomic and daily activities, exacerbates impaired strength and power in older adults with APOE ¿4 inheritance is unknown. Thus, we hypothesize that impaired motor function and greater fatigue among older adults is related to possession of the APOE ¿4 allele and mediated by reduced effectiveness of the glutamate receptor in motor cortical areas, reduced intracortical facilitation and decreased neural drive from motor cortical centers. Aim 1 will determine whether APOE ¿4 allele possession is associated with increased motor fatigue in lower limb muscles and decreased functionality of motor tasks (walking speed, balance, stair climbing) among independently living older men and women. Aim 2 will compare intracortical facilitation and neural drive from the motor cortex during motor function tasks before and after motor fatigue among older men and women who are carriers and non-carriers of APOE ¿4. Intracortical facilitation and supraspinal drive will be quantified with TMS of the motor cortex. Because older women are weaker and closer to functional performance thresholds without added vulnerability, sex differences will be explored to determine if older men or women are more vulnerable to motor impairment with APOE ¿4 inheritance associated with reduced intracortical facilitation and supraspinal drive. The results will have high impact by: (1) providing insight into successful aging and the mediating role of intracortical facilitation and supraspinal drive; (2) identifying 'healthy' but vulnerable older adults for accelerated motor decline, and (3) providing a rationale for early, targeted strategies to offset altered neural networks and early motor decline.

描述（由申请人提供）：运动功能与年龄相关的变异性增加表明，一些老年人比其他人更容易出现运动衰退。弱势成年人的运动功能受损，导致工作能力丧失和独立性丧失，最终导致老龄化社会的成本大幅增加。该提案采用了一种新的创新方法来了解易受伤害的老年男性和女性的运动功能和运动疲劳（运动引起的力量下降）。我们探索了随着年龄的增长而发生的巨大的受试者间变异，以深入了解男性和女性下肢运动衰退的遗传机制。具体来说，我们将运动功能和疲劳的受试者间变异与载脂蛋白-E ¿4 等位基因的遗传联系起来 （APOE）基因。我们认为，与 APOE ¿4 非携带者相比，APOE ¿4 携带者在运动皮质区域中谷氨酸受体 (NMDA) 的有效性降低，随后皮质内兴奋性降低，运动任务期间神经驱动力降低：这些机制将通过经颅磁刺激 (TMS) 进行评估。尽管对弱势老年人进行干预具有巨大的潜力，但运动衰退背后的皮质机制受到的关注却非常有限。 APOE ¿4 遗传通常与阿尔茨海默病的风险相关，但最近显示，随着年龄的增长，运动功能下降的风险会增加。动态任务期间的运动疲劳（这是人体工程学和日常活动的常见组成部分）是否会加剧患有 APOE ¿4 遗传的老年人的力量和爆发力受损，目前尚不清楚。因此，我们假设老年人运动功能受损和更严重的疲劳与拥有 APOE ¿4 等位基因有关，并由运动皮质区域谷氨酸受体的有效性降低、皮质内促进减少和运动皮质中心的神经驱动减少介导。目标 1 将确定 APOE ¿4 等位基因的拥有是否与独立生活的老年男性和女性下肢肌肉运动疲劳增加和运动任务功能（步行速度、平衡、爬楼梯）下降有关。目标 2 将比较 APOE 携带者和非携带者 ¿4 携带者和非携带者的老年男性和女性在运动疲劳前后的运动功能任务期间皮质内促进和来自运动皮层的神经驱动。皮质内促进和脊髓上驱动将通过运动皮质的 TMS 进行量化。由于老年女性较弱且更接近功能表现阈值而没有增加脆弱性，因此将探讨性别差异，以确定老年男性或女性是否更容易受到与皮质内促进和脊髓上驱动减少相关的 APOE 4 遗传性运动障碍的影响。结果将通过以下方式产生重大影响：（1）提供对成功衰老以及皮质内促进和脊髓上驱动的中介作用的见解； （2）识别“健康”但易受伤害的老年人加速运动衰退，以及（3）为早期、有针对性的策略提供理由，以抵消改变的神经网络和早期运动衰退。