Aortic stiffness, wave reflection, and cerebrovascular flow pulsatility: relations with brain small vessel disease and cognitive function in a middle-aged cohort

摘要 随着人口老龄化，阿尔茨海默病及相关痴呆症（ADRD）的患病率将增加 很明显。先前的研究表明，过度的主动脉僵硬是一种潜在的可改变的风险 ADRD因素。较高的主动脉僵硬度与脑小血管疾病相关， 被认为是调节僵硬和ADRD之间的关系。然而，特定的血流动力学机制 介导主动脉僵硬对大脑中小血管的有害影响的机制仅被部分理解。 主动脉硬化与脉动能量向颈动脉循环的传输增加有关。 当主动脉顺应时，它会缓冲与每次心跳相关的压力和流量波动。为 主动脉硬化，颈动脉中的压力和流动脉动显著增加。如果这些高度搏动的 压力和流量波形到达脑微循环，相关的过度脉动能量可 损伤大脑中脆弱的小血管。另一个潜在的机制涉及主动脉瓣的不良反应 心脏和主动脉之间的机械耦合硬化。当心脏收缩时，它会拉伸近端 主动脉像弹簧一样当心脏放松时，储存在“主动脉弹簧”中的能量会抬高心脏的底部 并促进心室充盈以准备下一次心跳。主动脉弹簧刚度过度增加 心脏负荷，损害心脏的收缩和舒张功能。因此，主动脉硬化可能代表 心脏健康和大脑健康之间已知关联的机械联系。 基于以下三个具体目标，我们将在审查4 深表型心脏病研究（FHS）第三代（G3），新后代配偶（NOS），和 少数Omni-2（O2）队列。目的1：检查主动脉僵硬度、颈动脉“脉动过滤器”、 测量颅内动脉的整体波反射、总动脉顺应性和主动脉Windkessel压， 用经颅多普勒超声评估大脑中动脉（MCA）的血流脉动性。目标二： 检查主动脉僵硬度测量与颈动脉和颅内MCA血流脉动的关系，a） 使用一种新的状态，通过磁共振成像评估脑微血管损伤的措施， 艺术模式分析和机器学习（PAML）方法和B）通过定量评估的认知功能 神经精神测试目的3：评估主动脉弹簧刚度和峰值主动脉应变力的关系， a）左心室结构和收缩及舒张功能，和B）颈总动脉平均流量， MCA血流脉动指数。我们将利用已经资助的基础和实验室核心FHS考试， 大脑成像和神经认知测试来评估这个关键的难题。我们的申请将通知 制定干预策略，限制对大脑微循环的损害，防止严重的 动脉僵硬度对脑结构、认知功能和ADRD事件的后续影响。

ABSTRACT As the population ages, the prevalence of Alzheimer’s disease and related dementias (ADRD) will increase markedly. Prior studies have shown that excessive aortic stiffness represents a potentially modifiable risk factor for ADRD. Higher aortic stiffness is associated with evidence of brain small vessel disease, which is thought to mediate the relation between stiffness and ADRD. However, specific hemodynamic mechanisms that mediate the harmful effects of aortic stiffness on small vessels in the brain are only partially understood. Stiffening of the aorta is associated with increased transmission of pulsatile energy into the carotid circulation. When the aorta is compliant, it buffers the pressure and flow swings associated with each heartbeat. As the aorta stiffens, pressure and flow pulsatility increase markedly in the carotid arteries. If these highly pulsatile pressure and flow waveforms reach the brain microcirculation, associated excessive pulsatile energy can damage fragile small vessels in the brain. Another potential mechanism involves adverse effects of aortic stiffening on mechanical coupling between heart and aorta. When the heart contracts, it stretches the proximal aorta like a spring. When the heart relaxes, energy stored in the “aortic spring” elevates the base of the heart and facilitates ventricular filling in preparation for the next heartbeat. Excessive aortic spring stiffness increases load on the heart and impairs systolic and diastolic function of the heart. Thus, aortic stiffening may represent a mechanistic link between known associations between heart health and brain health. With the following 3 specific aims, we will examine the foregoing mechanisms during examination 4 of the deeply phenotyped Framingham Heart Study (FHS) Third Generation (G3), New Offspring Spouse (NOS), and minority Omni-2 (O2) cohorts. Aim 1: Examine relations of aortic stiffness, the carotid “pulsatility filter,” measures of global wave reflection, total arterial compliance, and aortic Windkessel pressure with intracranial flow pulsatility in the middle cerebral artery (MCA) assessed with transcranial Doppler ultrasound. Aim 2: Examine relations of aortic stiffness measures and carotid and intracranial MCA flow pulsatility with a) measures of brain microvascular damage assessed by magnetic resonance imaging using a novel state-of-the- art pattern analysis and machine learning (PAML) method and b) cognitive function assessed by quantitative neuropsychiatric testing. Aim 3: Assess relations of aortic spring stiffness and peak aortic strain force and work with a) left ventricular structure and systolic and diastolic function, and b) common carotid mean flow and MCA flow pulsatility index. We will leverage the already funded basic and laboratory core FHS examinations, brain imaging, and neurocognitive testing to evaluate this critical conundrum. Our application will inform the development of intervention strategies that limit damage to the brain microcirculation and prevent the severe consequential effects of arterial stiffness on brain structure, cognitive function, and incident ADRD.