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: 10367312
• 负责人: Lidia Glodzik
• 金额: $ 82.35万
• 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/10367312
• 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; Atherosclerosis; Biological Markers; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Brain; Cephalic; Cerebrovascular Circulation; Chronic; Circle of Willis; Clinical Trials; Cognition; Cognitive; Data; Disease Marker; Enrollment; Evaluation; Failure; Goals; High Prevalence; Hippocampus (Brain); Hypertension; Hypoxia; Impairment; Inflammation; Lesion; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Motion; National Heart, Lung, and Blood Institute; Older Population; Outcome; Pathology; Pathway interactions; Perfusion; Play; Population; Positron-Emission Tomography; Randomized; Regulation; Reporting; Research; Resolution; Risk; Role; Slice; Testing; Time; United States National Institutes of Health; Variant; Vascular System; Vascular blood supply; abeta deposition; arterial spin labeling; base; blood pressure reduction; cerebrovascular; follow-up; human very old age (85+); hypertension control; hypertensive; hypoperfusion; innovation; novel; pressure; tau Proteins; tau aggregation; tau phosphorylation; 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.

概括 高血压 (HTN) 影响着超过 60% 的美国 60 岁以上人口。它会增加患阿尔茨海默病的风险 (AD) 通过脑血流 (CBF) 调节受损。多项研究未能证实 降低血压（BP）对认知和大脑测量有持续的好处。这大概是由于 血管系统先前存在的损害，无法适当补偿相对灌注 血压降低引起的压力下降。在上一个周期中，我们表明，在 HTN 中，存在一个最佳 BP 使 CBF 最大化的水平。我们还展示了 1) 降低白质病变风险的最佳血压，2) 灌注 与 tau 病理学相关，并且 3）所有这些发现都发生在老年 HTN 受试者中。尽管有这些新 研究发现，由于年龄和血压以外的因素，CBF 和认知存在很大差异，这表明 需要进一步微调模型以获得最佳BP。在我们 NIH/NHLBI R01 的竞争性更新中 HL111724 我们建议重点关注 Willis 圆 (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，人们对它们如何影响灌注、认知却知之甚少。 和 HTN 中的 AD 标记。我们的数据表明，不完整的变体在存在以下情况的情况下发挥作用： 已经存在血管系统（HTN）损伤。我们提供这些变体的设置 高血压需要更高的灌注压来维持足够的血流，从而增加了风险 低灌注和 AD 相关病理。 我们将在两年内招募 140 名 70-85 岁、认知健康的高血压受试者，其中 (n=70) 和 没有（n=70）奶牛的典型解剖结构。在基线和 24 个月随访时，我们将进行血压和认知检查 评估、磁共振成像（包括灌注和血管解剖）。团体中 50% 的人将 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：AIM1。 H1。对于相同的 BP，具有不完全 CoW 的受试者的 CBF 低于受试者 与一个完整的圆圈。 H2。纵向上，在具有不完整 CoW 的受试者中，对于相同的基线血压， 与具有完整圆的受试者相比，同等程度的血压降低意味着 CBF 的降低更大。目标2。 H1。对于 相同血压下，不完全 CoW 受试者的基线淀粉样蛋白和 tau 积累量高于受试者 与一个完整的圆圈。 H2。 AD 生物标志物与 CBF 相关。 H3。纵向上，在不完整的受试者中 CoW，对于相同的基线血压，同等程度的血压降低需要更多的淀粉样蛋白和 tau 蛋白积累 在具有完整圆的受试者中。次要目标。 H1。后循环的变体（不完全 后环、椎动脉发育不全）选择性地与下海马 CBF 和 H2 相关。更高 海马tau蛋白积累。 我们希望我们的研究能够有助于微调 HTN 管理并帮助发现一种新的 AD 风险。