Impact of cerebral anatomical variations on cerebral perfusion, cerebrovascular reactivity, and biomarkers of cognitive decline

项目总结 最佳的大脑健康需要有效的脑血管功能、充足的血流灌注和高度的反应能力 血液流动调节。如果其中任何一项或这些项的组合受到威胁，将会对 大脑健康。以往的研究表明，脑低灌注量和脑血管不足 对血管活性刺激的反应可能先于认知损害的发生。事实上，成年人有认知能力 包括血管性痴呆症和阿尔茨海默病在内的损害表现为脑血流灌注不足。然而， 大多数将低灌注率与认知联系起来的证据来自临床前模型，只有极少的 慢性脑低灌注如何影响人类脑血管控制的研究。因此， 迫切需要对人类认知衰退的病理生理学进行更多的研究。我们的预赛 数据显示，患有脑部解剖变异的成年人表现出脑血流灌注不足和减少 脑血管反应性。这一发现很重要，因为它为我们的调查团队提供了一组 具有大脑解剖变异的个体，该变异可能自然地模拟慢性大脑低灌流状态。 我们的主要假设是慢性低灌注率，由脑血管的特定变异引起 建筑，影响脑血流调节，从而增加认知障碍的风险。因此， 该应用程序的目标是研究人类慢性低灌注率模型，检查 代偿机制，以维持灌流，并确定对认知健康的潜在影响。为 每个目标，我们将从独特的、风险丰富的中老年人队列中招募参与者，这些人来自 威斯康星大学麦迪逊分校阿尔茨海默病研究中心。这一群体拥有广泛的 关于医疗健康、遗传学和认知生物标记物的纵向数据。我们将使用最先进的成像技术 识别脑血管构筑差异和量化脑血流调节的方法 具体目标：在具体目标1中，我们将研究急性心肌梗死模型的代偿性反应。 低灌注率和慢性脑低灌注率对成人特发性脑缺血的影响 大脑解剖变异。在具体目标2中，我们将利用有氧运动来表征 脑血管对急性高灌流的反应，并确定对大脑解剖变异的影响。 在特定的目标3中，我们将确定大脑解剖变异对脑血管控制和 确定患有大脑解剖变异的成年人是否有更高的认知能力下降风险。这个项目 将首次系统研究急性和慢性脑血管疾病的脑血管控制机制 人类的低灌流，并将解决长期低灌流对认知的潜在影响 健康。完成后，我们将了解大脑解剖变异对脑血管的影响 健康与阿尔茨海默病和相关痴呆症的风险。

PROJECT SUMMARY Optimal brain health requires effective cerebrovascular function, adequate perfusion, and highly responsive blood flow regulation. If any of these, or a combination of these, are compromised, there are implications for brain health. Previous research demonstrated that cerebral hypoperfusion and inadequate cerebrovascular responses to vasoactive stimuli may precede the onset of cognitive impairment. Indeed, adults with cognitive impairment, including vascular dementia and Alzheimer’s disease, exhibit inadequate cerebral perfusion. Yet, the majority of evidence linking hypoperfusion to cognition comes from preclinical models, and there is minimal research on how chronic cerebral hypoperfusion may impact cerebrovascular control in humans. Accordingly, there is a critical need for more research on the pathophysiology of cognitive decline in humans. Our preliminary data indicate that adults with cerebral anatomical variations demonstrate cerebral hypoperfusion and reduced cerebrovascular reactivity. This finding is important as it presents our investigative team with a group of individuals with a cerebral anatomical variant that may naturally model a state of chronic cerebral hypoperfusion. Our overarching hypothesis is that chronic hypoperfusion, resulting from a specific variation in cerebrovascular architecture, impacts cerebral blood flow regulation which increases the risk of cognitive impairment. Thus, the objectives of this application are to investigate chronic models of hypoperfusion in humans, examine compensatory mechanisms to maintain perfusion, and determine the potential impact on cognitive health. For each aim, we will recruit participants from a unique, risk-enriched cohort of middle-aged and older adults from the University of Wisconsin-Madison Alzheimer’s Disease Research Center. This cohort has extensive longitudinal data on medical health, genetics, and cognitive biomarkers. We will use state-of-the-art imaging modalities to identify differences in cerebrovascular architecture and quantify cerebral blood flow regulation in the following specific aims: In Specific Aim 1, we will examine the compensatory responses to a model of acute hypoperfusion and determine the impact of chronic cerebral hypoperfusion observed in adults with specific cerebral anatomical variations. In Specific Aim 2, we will utilize aerobic exercise to characterize the cerebrovascular responses to acute hyperperfusion and determine the impact of cerebral anatomical variations. In Specific Aim 3 we will determine the impact of cerebral anatomical variations on cerebrovascular control and establish whether adults with cerebral anatomical variations are at a higher risk of cognitive decline. This project will be the first systematic investigation of cerebrovascular control mechanisms in acute and chronic cerebral hypoperfusion in humans, and will address the potential implications of long-term hypoperfusion for cognitive health. Upon completion, we will understand the impact of cerebral anatomical variations on cerebrovascular health and the risk of Alzheimer’s disease and related dementias.