Accelerated Age-related Cognitive Decline: Impact of Exercise on Executive Function and Neuroplasticity (EXEC-study)

摘要： 老年人慢性肾脏病（CKD）存在于阿尔茨海默病和相关疾病谱中， 痴呆症（ADRD）比年龄和性别匹配的对照组早约10年。之时尚 在CKD老年人中，与年龄相关的认知能力下降和痴呆的加速率显著较高， 高达20- 50%。这一人群的认知障碍导致健康状况不佳， 药物和医疗护理依从性、功能下降和独立性加速丧失，以及 过早的制度化。慢性肾脏病患者与年龄相关的认知能力下降加速， 部分原因是CKD疾病过程本身，导致白色物质完整性降低， 叠加在包括海马萎缩的脑区域的加速神经变性上。 此外，肾功能下降与脑血流量降低独立相关，导致 脑灌注不足，进一步加剧认知能力下降。目前CKD的治疗方案 不包括预防认知能力加速下降和相关痴呆症的策略。可用 增强认知能力的药物疗法对减缓认知能力的影响只有适度的短期效果。 损害，具有不可耐受的副作用，并且需要在CKD患者中减少剂量。因此，有一个 迫切需要开发非药物疗法来预防或阻止老年人的认知能力下降 CKD有ADRD风险。本研究的目的是测试假设，6个月的家庭为基础的 在116名患有轻度认知障碍和CKD的老年人中进行步行锻炼计划， 功能，认知子域，大脑白色物质的完整性，结构和功能连接， 注意力控制我们将通过实现以下具体目标来实现这一目标。1：做运动 工作吗？量化执行认知功能（主要结局）和认知子域的变化。2.为 锻炼对谁有效？检查是否有因素（例如年龄、性别、认知障碍和共病） 条件）在6个月时认知功能领域的中度运动诱导的改善。3.如何 锻炼工作？使用MRI，我们将量化白色完整性从基线到6个月的变化， 功能连接、脑血流和灌注以及海马体积。我们还将评估 6个月时总运动量对认知功能领域和MRI测量的中介作用。我们 长期目标是制定以社区为基础的行为干预措施，以预防与年龄相关的认知障碍。 下降和ADRD在整个生命周期的风险人群。这项研究将解决一个关键的差距， 了解利用运动预防和治疗与年龄相关的认知加速 CKD和轻度认知功能障碍的老年人减少。通过结合认知功能评估 有了核磁共振成像，我们将能够评估大脑对运动的行为反应，并在一个特定的时间内辨别它们之间的关系。 以前没有在这个群体中进行过。潜在临床影响高且易于翻译。

Abstract: Older adults with chronic kidney disease (CKD) present on the spectrum of Alzheimer's Disease and Related Dementias (ADRD) approximately 10 years earlier than age and sex matched controls. The prevalence of accelerated age-related cognitive decline and dementia is remarkably high in older adults with CKD, affecting as many as 20-50%. Cognitive impairment in this population leads to poor health outcomes, decreased medication and medical care adherence, functional decline and an accelerated loss of independence, and premature institutionalization. The accelerated age-related cognitive decline in patients with CKD is due, in part, to the CKD disease process itself, which leads to a reduction in white matter integrity that is superimposed on accelerated neurodegeneration of brain regions including atrophy of the hippocampus. Moreover, reduced kidney function is independently associated with lower cerebral blood flow leading to cerebral hypoperfusion, which further exacerbates cognitive decline. Current treatment regimens for CKD do not include strategies to prevent accelerated cognitive decline and related dementia. The available pharmaceutical therapies to enhance cognition have only modest short-term effects on slowing cognitive impairment, have intolerable side effects, and require dose-reduction in CKD patients. Thus, there is a pressing need to develop non-pharmacological therapies to prevent or forestall cognitive decline in older adults with CKD at risk for ADRD. The objective of this study is to test the hypothesis that a 6-month home-based walking exercise program in 116 older adults with mild cognitive impairment and CKD will improve executive function, cognitive subdomains, brain white matter integrity, structure, and functional connectivity compared to attention control. We will achieve this objective by addressing the following specific aims. 1: Does exercise work? Quantify change in executive cognitive function (primary outcome), and cognitive subdomains. 2. For whom does exercise work? Examine if factors (e.g. age, sex, cognitive impairment, and, comorbid conditions) moderate exercise-induced improvement in cognitive function domains at 6-months. 3. How does exercise work? Using MRI we will quantify change from baseline to 6-months in white matter integrity, functional connectivity, cerebral blood flow and perfusion, and hippocampal volume. We will also evaluate the mediation effects of total exercise volume on cognitive function domains and MRI measures at 6-months. Our long-term goal is to develop community-based, behavioral interventions to prevent age-related cognitive decline and ADRD in at risk populations across the lifespan. This study will address a critical gap in our understanding of the use of exercise in the prevention and treatment of accelerated age-related cognitive decline in older adults with CKD and mild cognitive impairment. By combining cognitive function assessment with MRI, we will be able to evaluate the brain-behavior response to exercise and discern the relationships at a level previously not conducted in this population. The potential clinical impact is high and readily translatable.