Anatomy of the circle of Willis, cerebral blood flow, and Alzheimer's disease biomarkers in hypertension

高血压中威利斯环、脑血流量和阿尔茨海默病生物标志物的解剖

• 批准号: 10609842
• 负责人: Lidia Glodzik
• 金额: $ 81.57万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609842
• 关键词: Acute; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Anatomy; Antihypertensive Agents; Biological Markers; Blood Pressure; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Chronic; Circle of Willis; Circulation; Clinical Trials; Cognition; Cognitive; Compensation; Data; Disease Marker; Enrollment; Evaluation; Failure; Goals; High Prevalence; Hippocampus; Hypertension; Hypoxia; Impairment; Inflammation; Intracranial Atherosclerotic Disease; Lesion; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Motion; National Heart, Lung, and Blood Institute; Older Population; Outcome; Pathology; Pathway interactions; Perfusion; Population; Positron-Emission Tomography; Probability; Randomized; Regulation; Reporting; Research; Risk; Slice; Testing; Time; United States National Institutes of Health; Variant; Vascular System; Vascular blood supply; abeta deposition; arterial spin labeling; blood pressure reduction; cerebrovascular; follow-up; human very old age (85+); hypertension control; hypertensive; hypoperfusion; innovation; novel; pressure; tau Proteins; tau aggregation; tau-1; ultra high resolution; vertebral artery; white matter; white matter damage

SUMMARY Hypertension (HTN), affects over 60% of US population above 60. It increases the risk of Alzheimer's disease (AD) through compromised regulation of cerebral blood flow (CBF). Multiple studies failed to establish that lowering blood pressure (BP) entails consistent benefits for cognition and brain measures. This is probably due to a preexisting compromise of the vascular system, which does not compensate properly for relative perfusion pressure decrease caused by BP lowering. In a previous cycle, we showed that, in HTN, there is an optimal BP level that maximizes CBF. We also show 1) an optimal BP that decreases white matter lesion risk, 2) perfusion correlates with tau pathology, and 3) all these findings occur in older HTN subjects. Despite these new discoveries, there is a large variance in CBF and cognition due factors other than age and BP, suggesting the need for further fine-tuning of the model for optimal BP. In this competitive renewal of our NIH/NHLBI R01 HL111724 we propose to focus on variants of the circle of Willis (CoW). They adversely influence CBF and outcome in chronic and acute conditions. However, very little is known about how they affect perfusion, cognition and AD markers in HTN. Our data indicate that incomplete variants play a role in circumstances when there is already a pre-existing impairment of the vascular system (HTN). We offer that these variants in the setting of HTN necessitate higher perfusion pressure to maintain adequate blood flow, thus increasing the risk for hypoperfusion and AD-related pathology. Over a 2-year we will enroll 140 hypertensive, cognitively healthy subjects, 70-85 years old, with (n=70) and without (n=70) typical anatomy of the CoW. At baseline and 24-month follow-up, we will perform BP and cognition assessments, magnetic resonance imaging (including perfusion and vessel anatomy). 50% of the group will receive both tau (PI-2620) and amyloid (Neuraceq) positron emission tomography at baseline and follow-up. We will test whether: AIM1. H1. For the same BP, CBF is lower in subjects with an incomplete CoW than in subjects with a complete circle. H2. Longitudinally, in subjects with an incomplete CoW, for the same baseline BP, an equal reduction in BP entails greater reduction in CBF than in subjects with a complete circle. AIM2. H1. For the same BP, baseline amyloid and tau accumulation is higher in subjects with an incomplete CoW than in subjects with a complete circle. H2. AD biomarkers correlate with CBF. H3. Longitudinally, in subjects with an incomplete CoW, for the same baseline BP, an equal reduction in BP entails greater accumulation of amyloid and tau than in subjects who have a complete circle. Secondary AIM. H1. Variants of the posterior circulation (incomplete posterior circle, vertebral artery hypoplasia) are selectively related to lower hippocampal CBF, and to H2. higher hippocampal tau accumulation. We hope our research will contribute to fine-tuning of HTN management and help discover a novel AD risk.

总结 高血压（HTN）影响超过60%的60岁以上的美国人口。它会增加患老年痴呆症的风险 (AD)脑血流量（CBF）调节受损。多项研究未能证实 降低血压（BP）对认知和大脑测量具有一致的益处。这可能是由于 血管系统的预先存在的损害，其不能适当地补偿相对灌注 血压下降引起的血压下降。在前一个循环中，我们证明了在HTN中，存在最优BP 使CBF最大化。我们还显示了1）降低白色病变风险的最佳BP，2）灌注 与tau病理学相关，和3）所有这些发现都发生在老年HTN受试者中。尽管有这些新 发现，由于年龄和BP以外的因素，CBF和认知存在很大差异，这表明 需要进一步微调的最佳BP模型。在我们的NIH/NHLBI R 01的竞争性更新中， HL 111724我们建议关注Willis环（CoW）的变体。它们对CBF产生不利影响， 慢性和急性疾病的结果。然而，关于它们如何影响灌注，认知， 和AD标志物。我们的数据表明，不完整的变异发挥作用的情况下，当有 已经存在的血管系统损伤（HTN）。我们提出，这些变体在 HTN需要更高的灌注压来维持足够的血流，因此增加了 灌注不足和AD相关病理学。 在2年内，我们将招募140名高血压、认知健康的受试者，年龄70-85岁，（n=70）和 没有（n=70）典型的牛的解剖结构。在基线和24个月随访时，我们将进行BP和认知功能检查， 评估、磁共振成像（包括灌注和血管解剖）。50%的人会 在基线和随访时接受tau（PI-2620）和淀粉样蛋白（Neuraceq）正电子发射断层扫描。我们 将测试是否：AIM 1. H1。对于相同的BP，不完全CoW受试者的CBF低于受试者 一个完整的圆圈。H2。纵向上，在CoW不完整的受试者中，对于相同的基线BP， 血压同等程度的降低，其脑血流量的降低程度要大于环完整的受试者。目标2. H1。为 具有不完全CoW的受试者中的相同BP、基线淀粉样蛋白和tau蛋白蓄积高于具有不完全CoW的受试者中的相同BP、基线淀粉样蛋白和tau蛋白蓄积。 一个完整的圆圈。H2。AD生物标志物与CBF相关。H3.纵向上，在不完全 CoW，对于相同的基线BP，BP的同等降低需要比对照组更多的淀粉样蛋白和tau蛋白的积累。 有一个完整的圆圈。第二目标。H1。后循环变异（不完全） 后环、椎动脉发育不全）选择性地与海马下部CBF和H2相关。更高 海马tau蛋白积聚。 我们希望我们的研究将有助于HTN管理的微调，并帮助发现一种新的AD风险。