Hypertension, brain clearance and markers of neurodegeneration

项目总结 年龄是大脑疾病的最大风险因素，与错误折叠的蛋白质积累有关，而且 血管疾病的风险。到目前为止，几乎没有证据表明形成大脑的蛋白质的过度产生 神经退行性疾病中的沉积是导致其病理的原因。减少对大脑废物的清除 已经成为疾病发展的一个可能因素。脑血流量与血管 脉搏促进细胞外液体通过大脑，大脑是清除废物的通道。 我们认为，CBF和脑清除都依赖于脑血管的适当结构和健康。确实如此 血管状况是神经退行性变的重要危险因素。 虽然流行病学研究指出血管疾病是痴呆症的主要风险因素，但 证实相关的CBF减少，在人类中没有直接证据支持这一途径： 血管疾病血流动力学损害清除缺陷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)的方法来研究这一途径 估计大脑清除量的工具。在5年内，我们将对70名认知受试者进行为期24个月的纵向研究 60-80岁的健康受试者，基线分为：1)血压正常的NT(n=20)，2)对照组 高血压C-HTN组20例，未控制高血压或未治疗高血压UU-HTN组30例。我们的 目标是： AIM1.检测血管疾病(HTN)、脑血流量减少和脑清除障碍之间的关系 AIM2.研究HTN治疗是否能恢复脑血流量和改善脑清除 AIM3.测试HTN、CBF和脑清晰度是否能预测神经退行性变和认知的标志物 以及清除是否中介HTN和CBF对这些标记物的影响。 我们选择HTN是因为它是神经退行性疾病的常见危险因素。我们的前期工作 记录了它与血液动力学缺陷的关系，并表明与血液纵向减少有关 压力这些赤字可能是可逆的。作为神经退行性变的一个指标，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。到目前为止，广告是最 常见的与年龄相关的神经退行性疾病，我们已经报道了较高的血管负担与 更多不正常的AD生物标志物。 这个项目将增进我们对常见血管疾病如何影响大脑和 促进神经退化。高级成像和分析技术由经验丰富的 拥有长期合作记录的团队，允许对基本问题采取全面和新颖的方法。

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.