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

摘要 高血压(HTN)，影响美国60岁以上人口的60%以上。它会增加患阿尔茨海默病的风险 (AD)通过调节脑血流量(CBF)受损。多项研究都未能证实 降低血压(BP)对认知和大脑测量都有一致的好处。这很可能是因为 与先前存在的血管系统损害有关，这不能适当地补偿相对灌注 血压下降引起的压力下降。在前一个周期中，我们证明了在HTN中，存在一个最优BP 最大化CBF的级别。我们还显示了1)降低脑白质病变风险的最佳BP，2)血流灌注 与tau病理相关，3)所有这些发现都发生在老年HTN患者中。尽管有这些新的 发现，除了年龄和血压外，CBF和认知因素有很大的差异，这表明 需要对模型进行进一步微调，以获得最优BP。在我们的NIH/NHLBI R01的竞争更新中 HL111724我们建议关注Willis环(COW)的变体。它们对CBF和 在慢性和急性情况下的结果。然而，人们对它们如何影响灌流、认知却知之甚少。 HTN中的AD标志物。我们的数据表明，不完全变异在以下情况下发挥作用 已经存在的血管系统损害(HTN)。我们提供这些变种在 HTN需要更高的灌流压力来维持足够的血流量，因此增加了 低灌注率与AD相关病理。 在两年的时间里，我们将招募140名高血压、认知健康的受试者，年龄在70-85岁之间，(n=70)和 没有典型的奶牛解剖结构(n=70)。在基线和24个月的随访中，我们将进行BP和认知 评估、磁共振成像(包括灌注和血管解剖)。集团中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。对于相同的血压，患有不完全奶牛的受试者的CBF低于受试者 有一个完整的圆圈。H2。纵向上，在奶牛不完整的受试者中，对于相同的基线BP， 与完整循环的受试者相比，血压水平相同的受试者CBF的下降幅度更大。AIM2.H1。对于 同样的血压、基线淀粉样蛋白和tau在不完全奶牛的受试者中比受试者更高。 有一个完整的圆圈。H2。AD生物标志物与CBF相关。H3.在纵向上，在患有不完全 COW，对于相同的基线BP，相同的BP降低需要更多的淀粉样蛋白和tau的积累 在有完整圆圈的受试者中。二次瞄准。H1。后循环变异(不完全 后循环、椎动脉发育不良)选择性地与下海马区CBF和H2有关。更高 海马区tau蓄积。 我们希望我们的研究将有助于HTN管理的微调，并有助于发现一种新的AD风险。

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.