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

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受到运动能力下降的影响。脆弱成年人的运动功能受损，导致丧失工作能力和丧失独立性，最终导致老龄化社会付出更大的代价。这项建议采用了一种新的创新方法来了解脆弱的老年男性和女性的运动功能和运动疲劳(运动导致的强度降低)。我们探索随着年龄的增长而发生的巨大的受试者间变异性，以提供对男性和女性下肢运动下降背后的遗传机制的洞察力。具体地说，我们将运动功能和疲劳的受试者间变异性与载脂蛋白-E的？4等位基因的遗传联系起来 (ApoE)基因。我们认为，与非APOE？4携带者相比，APOE？4携带者运动皮质区域谷氨酸受体(NMDA)的有效性降低，皮质内兴奋性降低，神经驱动力降低：这些机制将通过经颅磁刺激(TMS)进行评估。尽管对脆弱的老年人进行干预有很大的潜力，但运动功能下降背后的皮质机制受到的关注非常有限。遗传通常与阿尔茨海默病的风险有关，但最近的研究表明，随着年龄的增长，运动功能下降的风险会增加。运动性任务中的运动疲劳是人体工程学和日常活动的一个常见组成部分，目前尚不清楚是否会加剧APOE遗传的老年人的力量和力量受损。因此，我们假设，老年人的运动功能受损和更严重的疲劳与APOE？4等位基因的拥有有关，并由运动皮质区域谷氨酸受体的有效性降低、皮质内便利性降低和运动皮质中心的神经驱动减少所介导。目的1将确定在独立生活的老年男性和女性中，APOE？4等位基因的拥有是否与下肢肌肉运动疲劳增加和运动任务(行走速度、平衡、爬楼梯)功能降低有关。目的2比较老年男性和女性APOE携带者和非携带者在运动疲劳前后运动功能任务中皮质内促进和神经驱动的差异。皮质内促进和脊髓上驱动将用运动皮质的TMS进行量化。由于老年女性在不增加脆弱性的情况下更虚弱，更接近功能表现阈值，因此将探索性别差异，以确定老年男性或女性是否更容易受到运动障碍的影响，APOE？4遗传与皮质内促进和脊髓上驱动力降低相关。这些结果将产生重大影响，因为：(1)提供了对成功衰老以及皮质内促进和脊髓上驱动力的中介作用的洞察；(2)找出了加速运动下降的“健康”但脆弱的老年人；以及(3)为早期、有针对性的策略提供了理论基础，以抵消神经网络改变和早期运动下降的影响。

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.