Examining a dose-dependent exercise intervention on cerebrovascular plasticity in late adulthood

摘要： 有氧运动（AE）是最有前途、最容易获得、最具成本效益的减少肥胖的方法之一。 阿尔茨海默病（AD）和相关痴呆症（ADRD）的风险，以及改善大脑健康和认知能力 在老年人中。然而，我们并不完全了解AE诱导的细胞内变化的机制， 大脑改善认知能力，降低转变为认知障碍的可能性。脑血管 改变随着年龄的增长而进展，并已被确定为与认知功能相关的主要因素之一。 下降因此，我们认为， 一个主要的假设是AE可以改变与年龄相关的脑血管疾病， 恶化 通过反复训练积累长期适应能力。这些 脑血管变化可介导大脑结构和功能的改善， 认知能力的提高。然而，我们仍然没有完全理解这些可能的机制， 最有效的剂量，以最大限度地改善脑血管。为了评估脑血管变化 以及它们与AE干预后大脑结构和功能变化的关系， 建议使用有氧运动的III期随机临床试验（RCT）进行次要数据分析 这项运动名为“运动干预试验中神经认知的获益调查”（IGNITE）。的 IGNITE研究包括12个月监督练习的干预前后评估 648名65 - 80岁认知正常的成年人。参与者被随机分配到 3个不同剂量组之一（每组n=213）：（i）150分钟/周的中等强度AE（公共卫生 推荐剂量），（ii）225分钟/周的中等强度AE条件，和（iii）拉伸对照 150分钟/周。我们将测试（1）12个月的AE随机对照试验是否会改变脑血管 搏动和血流，以及这些变化是否介导认知的改善，（2）AE- 诱导的脑血管变化介导脑萎缩、功能连接的改善， WMH增长。我们还将测试是否有任何影响与预先存在的健康状况有关，例如 高血压和 2型糖尿病，与AD/ADRD风险相关，并与AD病理学相关（例如， Ab和tau） .我们还将研究生物性别是否会调节目标1和目标2中的结果。 我们 假设接受225分钟/周的组将显示最大的脑血管改善， 这些改善介导了大脑结构和功能的变化。我们还期待着 AE引起的脑血管改善将以区域特异性方式发生，并导致领域特异性 与这些领域相关的认知改善。这项建议采用了一种成本效益很高的方法 通过关注NIH资助的随机对照试验的二级数据分析，因此符合NIA的使命 使用现有队列的数据来解决有关运动如何预防认知能力下降的重要问题 在晚年。这些发现可以建立一个管理年龄相关脑血管变化的框架， 参与定期AE，并可以提供公共政策指导，以使用锻炼作为一种方法， 降低与血管导致认知障碍和痴呆（VCID）相关的风险。的 这项研究的结果也可能导致更有效的预防和治疗策略，以减少 AD/ADRD的负担。

Abstract: Aerobic exercise (AE) is one of the most promising, accessible, and cost-effective methods for reducing risk for Alzheimer's disease (AD) and related dementias (ADRD), and for improving brain health and cognition in older adults. However, we do not fully understand the mechanisms by which AE-induced changes in the brain improve cognition and reduce the likelihood of transitioning to cognitive impairment. Cerebrovascular alterations progress with aging and have been identified as one of the primary factors associated with cognitive decline. Therefore, one leading hypothesis is that AE can modify aging-associated cerebrovascular deteriorations by accumulating long-term adaptations through repeated training sessions. These cerebrovascular changes could mediate improvements in structure and function in the brain, and associate with cognitive improvement. However, we still do not fully understand these possible mechanisms, nor the most effective doses to maximize cerebrovascular improvements. In order to assess cerebrovascular changes and their relationship with structural and functional brain changes in response to an AE intervention, we propose to conduct a secondary data analysis using a Phase III randomized clinical trial (RCT) of aerobic exercise called Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE). The IGNITE study included pre- and post-intervention assessments from a 12-month supervised exercise intervention in 648 cognitively normal adults between 65 and 80 years of age. Participants were randomized to one of 3 different dosage groups (n=213 each): (i) a moderate intensity AE of 150 min/week (the public-health recommended dose), (ii) a moderate intensity AE condition of 225 min/week, and (iii) a stretching control condition of 150 min/ week. We will test (1) whether a 12-month RCT of AE modifies cerebrovascular pulsatility and blood flow and whether these changes mediate improvements in cognition, (2) whether AE- induced cerebrovascular changes mediate improvements in brain atrophy, functional connectivity, and reduce WMH growth. We will also test whether any effects are associated with pre-existing health status, such as hypertension and type2 diabetes, which are associated with risk for AD/ADRD and linked to AD pathology (e.g. Ab and tau) . We will also examine whether biological sex moderates the results found in aims 1 and 2. We hypothesize that the group receiving 225 min/week will show the greatest cerebrovascular improvements and that these improvements mediate structural and functional brain changes. We also expect that the cerebrovascular improvements with AE will occur in region-specific manner and lead to domain-specific cognitive improvements that are related to those areas. This proposal employs a highly cost-effective approach by focusing on the secondary data analysis of an NIH-funded RCT and is therefore in line with the NIA mission to use data from existing cohorts to address important questions about how exercise prevents cognitive decline in late life. These findings could establish a framework for managing age-related cerebrovascular changes by participation in regular AE and could provide public policy guidance for using exercise as an approach for mitigating risks associated with vascular contributions to cognitive impairment and dementia (VCID). The results from this research could also lead to more effective preventive and therapeutic strategies to decrease the burden of AD/ADRD.