Hypertension, brain clearance and markers of neurodegeneration

项目摘要 年龄是与错误折叠蛋白质积累有关的脑部疾病的最大风险因素， 血管疾病的风险。到目前为止，几乎没有证据表明，过量生产的蛋白质形成大脑 神经变性病症中的沉积物有助于它们的病理学。减少大脑废物的清除 已经成为疾病发展的潜在因素。脑血流量（CBF）和血管 脉动促进细胞外液通过大脑，这是一个用于清除废物的通道。 我们认为，CBF和脑清除率取决于适当的结构和健康的脑血管。确实 血管疾病是神经变性的重要危险因素。 虽然流行病学研究指出血管疾病是痴呆症的主要危险因素， 证实相关的CBF减少，在人类中没有直接证据支持该途径： 血管疾病、血流动力学损害、清除障碍、神经变性 我们建议使用我们新开发的基于正电子发射断层扫描（PET）的 评估大脑清除率的工具。在5年的时间里，我们将对70名认知障碍者进行为期24个月的纵向研究。 60-80岁的健康受试者，在基线时分为：1）血压正常的NT（n=20），2）对照组 C型高血压20例; 3型高血压未控制或未治疗的UU型高血压30例。我们 目标是： AIM 1.检测血管疾病（HTN）、CBF降低和脑清除率受损之间的关系 目标2.检查HTN治疗是否恢复CBF并改善脑清除率 AIM3.测试HTN、CBF和脑清除率是否可预测神经变性和认知功能障碍的标志物。 性能以及清除是否介导HTN和CBF对这些标志物的影响。 我们选择HTN，因为它是神经退行性疾病的常见风险因素。我们的前期工作 记录了其与血流动力学缺陷的相关性，并表明血液中的纵向减少 压力这些赤字可能是可逆的。作为神经退行性变的指标，我们将使用脑脊液t- tau/aβ42比率（总tau/淀粉样蛋白β-42）-阿尔茨海默病（AD）的生物标志物。AD是迄今为止 常见的与年龄相关的神经退行性疾病，我们已经报道了更高的血管负荷与 更多异常的AD生物标志物。 该项目将促进我们对常见血管疾病如何影响大脑的理解， 促进神经退化先进的成像和分析技术，由经验丰富的 有着长期合作记录团队可以对基本问题采取全面和新颖的办法。

PROJECT SUMMARY Age is the strongest risk factor for brain diseases related to accumulation of misfolded proteins and also the risk for vascular diseases. So far, there is little evidence that excessive production of proteins forming brain deposits in neurodegenerative conditions contributes to their pathology. A reduced clearance of brain waste has emerged as a possible factor underlying disease development. Cerebral blood flow (CBF) and vascular pulsations facilitate the passage of extracellular fluid through the brain, a channel for removing waste products. We contend that both CBF and brain clearance depend on proper structure and health of brain vessels. Indeed vascular conditions are significant risk factors for neurodegeneration. Although epidemiological studies point out to vascular disease as a major risk factor for dementia, and corroborate related CBF reductions, there is no direct evidence in humans supporting the pathway: vascular disease  hemodynamic impairment  clearance deficit  neurodegeneration We propose to examine this pathway, using our newly developed Positron Emission Tomography (PET)-based tool to estimate brain clearance. Over 5 years we will conduct a 24-month longitudinal study of 70 cognitively healthy subjects 60-80 years old, classified at baseline into: 1) normotensive NT (n=20), 2) controlled hypertension C-HTN (n=20), 3) Uncontrolled hypertension or Untreated hypertension UU-HTN (n=30). Our goals are: AIM1. To test the relationship between vascular disease (HTN), reduced CBF and impaired brain clearance AIM2. To examine whether treatment of HTN restores CBF and improves brain clearance AIM3. To tests whether HTN, CBF and brain clearance predict markers of neurodegeneration and cognitive performance and whether clearance mediates the effects of HTN and CBF on these markers. We chose HTN since it is a common risk factor for neurodegenerative diseases. Our preliminary work documented its association with hemodynamic deficits, and showed that with longitudinal reduction in blood pressure these deficits may be reversible. As an index of neurodegeneration we will use cerebrospinal fluid t- tau/aβ42 ratio (total tau/ amyloidβ-42) – a biomarker of Alzheimer's disease (AD). AD is by far the most common age-related neurodegenerative disease and we have reported that higher vascular burden is related to more abnormal AD biomarkers. This project will advance our understanding of how common vascular condition affects the brain and facilitates neurodegeneration. Advanced imaging and analytical techniques implemented by an experienced team with a long record of collaboration, permit a comprehensive and novel approach to essential questions.