Arterial aging, brain perfusion & exercise: impact on brain structure & function.

描述（由申请人提供）：高龄是认知能力下降的主要风险因素。越来越多的证据表明，身体活动对保持老年人大脑健康的重要性。然而，目前，我们对潜在的机制知之甚少。动脉硬化和中心脉压的增加是动脉老化的标志，这可能对脑灌注有显著影响。本提案的总体目标是检验中心假设，即运动训练通过改变动脉老化改善脑灌注，这些变化导致局部脑容量增加和白色病变减少，从而改善65岁以上老年人的认知功能。将实现以下具体目标：1）确定动脉硬度和中心脉压随年龄的增加是否与脑血管阻力/阻抗增加、脑灌注减少和脑血管功能障碍相关; 2）确定运动训练是否通过改变动脉老化来改善脑灌注，如脑血管阻力/阻抗，动脉硬度，中枢脉压和/或血管内皮功能的改善; 3）确定运动训练对脑灌注的改善是否导致局部脑体积的增加、白色物质病变的减少和认知功能的改善。为了实现这一目标，将针对目标1进行青年、中年和老年人的横断面研究。此外，还将针对目标2和3在老年人中进行为期一年的有氧运动训练和控制（灵活性和平衡训练）的纵向研究。最先进的经颅多普勒和磁共振成像将用于测量脑灌注和结构的变化。一套对年龄敏感的综合神经心理学测试将用于测量认知功能的变化。将使用多元回归和中介模型分析的先进统计方法来确定动脉老化、脑灌注、结构和认知功能之间的关系。 公共卫生相关性：高龄是认知能力下降的主要危险因素。随着老年人在总人口中所占比例的增加，与年龄有关的认知障碍，如阿尔茨海默病（AD）和其他类型的痴呆症的患病率也在上升。因此，深入了解大脑衰老的机制并开发预防性干预措施以保持认知健康是21世纪世纪最大的社会和科学挑战之一。这项建议将确定有氧运动训练是否增加大脑灌注，从而改善老年人的大脑结构和认知功能。此外，我们将确定这些变化是否是通过改变动脉老化介导的。获得的新知识将提供深入了解运动保持大脑健康的血管机制。实际上，新发现对于开发新策略以保持随着年龄增长的认知活力具有潜在的重要性。

DESCRIPTION (provided by applicant): Advanced age is a major risk factor for cognitive decline. Accumulating evidence demonstrates the importance of physical activity for preserving brain health in older adults. However, at present, we know very little about the underlying mechanisms. Arterial stiffening and increases in central pulse pressure are the hallmark of arterial aging which may have significant impact on brain perfusion. The overall objective of this proposal is to test the central hypothesis that exercise training improves brain perfusion by modifying arterial aging and these changes lead to increases in regional brain volume and reductions in white matter lesions, and thus improvement in cognitive function in older adults over 65. The following specific aims will be accomplished: 1) to determine whether increases in arterial stiffness and central pulse pressure with age are associated with increases in cerebrovascular resistance/impedance, reduction in brain perfusion and cerebrovascular dysfunction; 2) to determine whether exercise training improves brain perfusion by modifying arterial aging as indicated by reductions in cerebrovascular resistance/impedance, arterial stiffness, central pulse pressure and/or improvement in vascular endothelial function; 3) to determine whether improvement in brain perfusion with exercise training leads to increases in regional brain volume, reductions in white matter lesions and improvement in cognitive function. To accomplish this goal, a cross-sectional study of the young, middle-aged and elderly individuals will be conducted for aim 1. Furthermore, a longitudinal study of aerobic exercise training and control (flexibility and balance training) will be conducted for one year in the elderly for aim 2 and 3. The state-of-the-art transcranial Doppler and magnetic resonance imaging will be used to measure changes in brain perfusion and structure. A comprehensive battery of neuropsychological testing sensitive to age will be used to measure changes in cognitive function. Advanced statistical methods of multiple variable regression and mediation model analysis will be used to determine the relationship between arterial aging, brain perfusion, structure and cognitive function. PUBLIC HEALTH RELEVANCE: Advanced age is a major risk factor for cognitive decline. With the growing share of older adults in the general population, the prevalence of age-related cognitive disorders, such as Alzheimer's disease (AD) and other types of dementia, is also on the rise. Thus, in-depth understanding of the mechanisms of brain aging and developing preventive interventions to maintain cognitive health is one of the biggest social and scientific challenges for the 21st century. This proposal will determine whether aerobic exercise training increases brain perfusion leading to improvement in brain structure and cognitive function in the elderly. Furthermore, we will determine whether these changes are mediated by modifying arterial aging. The new knowledge obtained will provide in-depth understanding the vascular mechanisms for exercise preserving brain health. Practically, the new findings are potentially important for developing new strategies to maintain cognitive vitality with age.