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

摘要： 阿尔茨海默病及其相关的老年慢性肾脏病(CKD) 痴呆症(ADRD)比年龄和性别匹配的对照组早大约10年。疾病的流行 在患有CKD的老年人中，与年龄相关的认知功能减退和痴呆症的加速发生率非常高，影响 高达20%-50%。这一人群的认知障碍会导致不良的健康结果，减少 服药和医疗护理依从性、功能衰退和独立性加速丧失 过早地将其制度化。慢性肾脏病患者年龄相关性认知功能减退的加速是由于 部分，与CKD疾病过程本身有关，这导致脑白质完整性降低，即 叠加在脑区加速的神经变性上，包括海马体的萎缩。 此外，肾功能降低与脑血流量降低独立相关，从而导致 大脑灌流不足，进一步加剧认知能力下降。CKD DO的当前治疗方案 不包括预防认知加速衰退和相关痴呆症的策略。可用的 增强认知的药物疗法对减缓认知能力只有温和的短期效果 对慢性肾脏病患者来说，这种药物有不可耐受的副作用，需要减少剂量。因此，有一个 迫切需要开发非药物疗法来预防或预防老年人的认知衰退 CKD面临ADRD的风险。这项研究的目的是检验这样一种假设，即以家庭为基础的6个月 116名轻度认知障碍和CKD老年患者的步行锻炼计划将改善执行力 功能、认知亚域、脑白质完整性、结构和功能连通性 注意控制。我们将通过处理以下具体目标来实现这一目标。1.锻炼身体吗？ 工作?量化执行认知功能(主要结果)和认知子领域的变化。2. 锻炼的对象是谁？检查因素(例如，年龄、性别、认知障碍和共病 条件)在6个月时适度运动导致认知功能领域的改善。3.如何 锻炼身体？使用核磁共振，我们将量化从基线到6个月白质完整性的变化， 功能连通性，脑血流和灌注量，以及海马体体积。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。我们的 长期目标是开发基于社区的行为干预措施，以防止与年龄相关的认知 高危人群在整个寿命期间的下降和ADRD。这项研究将解决我们在 运动在防治年龄相关性认知加速障碍中的应用 患有慢性肾脏病和轻度认知障碍的老年人下降。通过结合认知功能评估 通过核磁共振成像，我们将能够评估大脑对运动的行为反应，并在 以前在这一人群中没有进行过的水平。潜在的临床影响很大，而且很容易翻译。

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.