Hypertension, intracranial pulsatility and brain A-beta accumulation in older adults

项目总结/摘要 最近在啮齿动物中的研究表明，存在一个全脑胶质淋巴系统， 脑脊液（CSF）从蛛网膜下腔通过帕拉核流入脑实质， 动脉和静脉旁间隙。这种CSF流冲洗出间质可溶性Aβ，tau和其他有毒蛋白， 最终影响脑Aβ和tau蛋白稳态。颅内搏动的存在是 被认为是CSF通过这些途径对流的驱动力。然而，无论这 在人类中类似的机制功能仍然未知。高血压加速大脑衰老， 增加患阿尔茨海默病（AD）的风险。根本的机制还不清楚。我们 最近的研究和其他研究表明，中枢搏动性升高与脑萎缩有关 和白色病变。中枢搏动性的变化是如何向下游传递到大脑的 微循环产生颅内搏动，以及颅内搏动的变化是否影响脑 Aβ和tau稳态也仍然未知。这个项目的首要目标是测试 强化抗高血压治疗改变中枢和颅内搏动性的假设， 进而影响脑内Aβ和tau蛋白的稳态。此外，我们将确定是否有变化， 颅内搏动、Aβ和tau蛋白与脑白色物质完整性和神经网络相关 功能性连接。为了实现这一目标，我们将招募120名60-79岁的老年人。其中，40人 正常血压（24 h收缩压<130/80 mmHg）80例，高收缩压（24 h收缩压≥140）80例。患者 高血压患者将随机分为12个月强化治疗组（24小时SBP≤125）和对照组（24小时SBP≤125）。 标准治疗组（24小时SBP≤140）。目的1：确定高血压对颅内压的影响 脉动性、CSF Aβ和tau、脑白色物质完整性和神经网络功能连接。 假设：高血压与以下因素相关：1）中枢搏动增强，但颅内压降低 脉动性; 2）CSF可溶性Aβ42减少，但磷酸化tau和总tau增加; 3）破坏 通过扩散张量成像推断脑白色物质完整性，通过静息状态推断功能连接性 功能磁共振成像。我们还将确定颅内搏动性、脑Aβ和tau蛋白的组间差异是否是 与白色物质完整性和神经网络功能连接相关;目的2：确定影响 抗高血压治疗对颅内搏动性、CSF Aβ和tau蛋白、脑白色物质完整性和 神经网络功能连接假设：与标准治疗相比，强化治疗 更多受益：1）中枢搏动性降低，但颅内搏动性增加; 2）CSF增加 Aβ42，但磷酸化tau和总tau减少; 3）改善脑白色物质完整性， 神经网络功能连接

Project Summary/Abstract Recent studies in rodents demonstrate the existence of a brain-wide glymphatic system, which transports bulk flow of cerebrospinal fluid (CSF) from the subarachnoid space into the brain parenchyma through the para- arterial and para-venous spaces. This CSF flow flushes out interstitial soluble Aβ, tau and other toxic proteins, ultimately influencing brain Aβ and tau protein homeostasis. The presence of intracranial pulsatility is recognized as the driving force for the convection of CSF through these pathways. However, whether this mechanism functions similarly in humans remains unknown. Hypertension accelerates brain aging and increases the risk of Alzheimer's disease (AD). The underlying mechanism(s) are not well understood. Our recent studies and others have demonstrated that elevated central pulsatility is associated with brain atrophy and white matter lesions. How changes in central pulsatility are transmitted downstream into cerebral microcirculation to generate intracranial pulsatility, and whether changes in intracranial pulsatility affect brain Aβ and tau homeostasis also remain unknown. The overarching goal of this project is to test the hypothesis that intensive antihypertensive treatment alters central and intracranial pulsatility which in turn affect brain Aβ and tau protein homeostasis. Furthermore, we will determine whether changes in intracranial pulsatility, Aβ and tau are associated with brain white matter integrity and neural network functional connectivity. To achieve this goal, we will enroll 120 older adults age 60-79. Of those, 40 have normal blood pressure (BP) (24-h BP<130/80 mmHg) and 80 have high systolic BP (24-h SBP ≥140). Patients with hypertension will be randomized into a 12-month intensive treatment arm (24-h SBP≤125) and a control arm of the standard care (24-h SBP≤140). Aim 1: Determine the effects of hypertension on intracranial pulsatility, CSF Aβ and tau, brain white matter integrity, and neural network functional connectivity. Hypotheses: Hypertension is associated with: 1) augmented central pulsatility, but reduced intracranial pulsatility; 2) reductions in CSF soluble Aβ42, but increases in phosphorylated tau and total tau; 3) disruptions in brain white matter integrity inferred by diffusion tensor imaging, and functional connectivity by resting-state fMRI. We also will determine whether group differences in intracranial pulsatility, brain Aβ, and tau are associated with white matter integrity and neural network functional connectivity; Aim 2: Determine the effects of antihypertensive treatments on intracranial pulsatility, CSF Aβ and tau, brain white matter integrity and neural network functional connectivity. Hypotheses: compared to standard care, intensive treatment confers more benefits by: 1) reductions in central pulsatility, but increases in intracranial pulsatility; 2) increases in CSF Aβ42, but reductions in phosphorylated tau and total tau; 3) improvement in brain white matter integrity and neural network functional connectivity.