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，阿尔茨海默病和相关痴呆(ADRD)的患病率将会增加 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的影响因素。较高的主动脉僵硬与脑部小血管疾病的证据有关，这是 考虑调节刚性与ADRD之间的关系。然而，特定的血流动力学机制 对于主动脉僵硬对大脑小血管的有害影响，目前还只有部分了解。 主动脉硬化与脉动能量进入颈动脉循环的传递增加有关。 当主动脉顺应性时，它会缓冲与每一次心跳相关的压力和流量波动。作为 颈动脉内动脉变硬，压力和血流搏动性显著增加。如果这些高度脉动的 压力和血流波形到达大脑微循环，相关的过度脉动能量可以 破坏大脑中脆弱的小血管。另一种可能的机制涉及到主动脉的不良反应 心脏和主动脉之间机械耦合的僵硬。当心脏收缩时，它会伸展近端 大动脉像弹簧一样。当心脏放松时，储存在“主动脉弹簧”中的能量会抬高心脏底部。 并有助于心脏充盈，为下一次心跳做准备。过多的主动脉弹簧僵硬会增加 心脏负荷，损害心脏的收缩和舒缩功能。因此，主动脉硬化可能代表一种 心脏健康和大脑健康之间已知的关联之间的机械联系。 带着以下三个具体目标，我们将在第四次审查期间审查上述机制 深度表型Framingham心脏研究(FHS)第三代(G3)，新生配偶(NOS)，以及 少数Omni-2(O2)队列。目的1：检查主动脉僵硬、颈动脉“搏动性滤器”、 用颅内测量整体波反射、总动脉顺应性和主动脉温克塞尔压 经颅多普勒超声检测大脑中动脉(MCA)血流搏动性。目标2： 检查主动脉僵硬指标与颈动脉和颅内大脑中动脉血流搏动的关系 使用一种新的状态-磁共振成像评估脑微血管损伤的测量- 艺术模式分析和机器学习(PAML)方法和b)认知功能的量化评估 神经精神测试。目的3：评价主动脉弹簧刚度与最大应变力的关系。 研究a)左心室结构以及收缩和舒张期功能，以及b)颈总动脉平均血流和 大脑中动脉血流搏动指数。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一关键难题。我们的应用程序将通知 制定干预策略，限制对大脑微循环的损害，防止严重的 动脉僵硬对大脑结构、认知功能和ADRD事件的相应影响。

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.