Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid and Tau in Older Adults (IPAT-study)

强化降压治疗对老年人脑血流灌注、淀粉样蛋白和牛磺酸的影响 成人(IPAT-研究) 项目摘要 最近，NIA-AA研究框架将AD定义为异常积累的生物结构 大脑中的Aβ和tau蛋白。同样，脑血管对阿尔茨海默病的重要性 发病机制现已得到充分认识。高血压是脑血管疾病的主要原因；70%的人 65岁或以上的成年人患有高血压。Sprint试验表明，强化治疗高血压 降低认知障碍或痴呆症的风险。然而，潜在的机制尚不清楚。 高血压及其相关动脉硬化损害局部脑血流量(CBF)，减少 脑白质完整性，并通过大脑淋巴系统影响大脑淀粉样蛋白和tau的清除。我们的 研究还表明，高血压和中央动脉僵硬与大脑呈正相关。 用正电子发射计算机断层扫描测量β负荷，血氧水平低频波动的幅度- RS-fMRI测量的依赖信号与老年人脑淀粉样蛋白负荷呈负相关 成人，提示它在大脑Aβ调节中的作用。该项目的首要目标是确定 是否将收缩压(SBP)密集降至120毫米汞柱的目标， &lt；140毫米汞柱，减少患痴呆症高危老年人的大脑淀粉样蛋白和tau。 此外，我们将确定血压降低对CBF、动脉僵硬、粗大Alff、白色的影响 物质高强度(WMH)、脑网络连接和神经认知功能，以及 这些变化与脑淀粉样蛋白和tau的关系。我们将招收180名60岁至80岁的老年人 有高血压(SBP≥130毫米汞柱)、痴呆症FH和/或主观记忆主诉的患者。 参与者将被随机分为强化治疗组(SBP&lt；120 mm Hg)或常规护理组(SBP&lt；140 mm Hg)。 并跟踪了2年，以实现以下具体目标：1)确定 强化降压对脑淀粉样蛋白、tau蛋白和神经认知功能的影响。假设：密集的SBP 与平时的护理相比，降低血压可以减少大脑Aβ和tau沉积的进展； Tau与神经认知功能相关。2)确定强化降压对脑血流量的影响。 中央动脉僵硬，和大胆的阿尔夫。假设：密集降低SBP降低中央动脉 僵硬和增加局部CBF和BOLD ALF；CBF、动脉僵硬和BOLD ALF的变化 与脑A、β、tau相关。3)探讨强化降压对脑WMH、WITH的影响 物质微观结构的完整性和神经网络的连通性。假设：密集降低SBP可降低血压 大脑WMH的进展，改善脑白质微结构完整性和脑网络连接 它们与大脑A、β和tau的变化有关。所获得的新知识将提供机械论 对高血压、脑血管功能和AD病理生理学之间关系的洞察 对发展痴呆预防和治疗的多领域战略具有潜在的重要意义。

Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid and Tau in Older Adults (IPAT-study) Project Summary Recently, the NIA-AA research framework has defined AD as a biological construct of abnormal accumulation of Aβ and tau proteins in the brain. Similarly, the importance of cerebrovascular contributions to AD pathogenesis is now well recognized. Hypertension is the leading cause of cerebrovascular disease; >70% of adults aged 65 or older have hypertension. The SPRINT trial showed that intensive treatment of hypertension reduced risk of cognitive impairment or dementia. However, the underlying mechanisms are unclear. Hypertension and the associated arterial stiffening compromise regional cerebral blood flow (CBF), reduce brain white matter integrity, and impact brain amyloid and tau clearance via the brain glymphatic system. Our studies also showed that high blood pressure and central arterial stiffness are associated positively with brain Aβ burden measured with PET and that the amplitude of low frequency fluctuations of blood-oxygen-level- dependent signal measured with rs-fMRI (BOLD ALFF) is correlated negatively brain amyloid burden in older adults, suggesting its role in brain Aβ regulation. The overarching goal of this project is to determine whether intensive lowering of systolic blood pressure (SBP) to a target of <120 mmHg, compared with <140 mmHg, reduces brain amyloid and tau in older adults who are at high risk of dementia. Furthermore, we will determine the impact of BP lowering on CBF, arterial stiffness, BOLD ALFF, white matter hyperintensity (WMH), brain network connectivity, and neurocognitive function, as well as the relationships of these changes with brain amyloid and tau. We will enroll 180 older adults age 60 to 80 years who have hypertension (SBP≥130 mmHg), FH of dementia, and/or subjective memory complaints. Participants will be randomized into the intensive treatment (SBP<120 mmHg) or usual care (SBP<140 mmHg) arms and followed for 2 years to accomplish the following specific aims: 1) To determine the effects of intensive SBP lowering on brain amyloid, tau, and neurocognitive function. Hypotheses: Intensive SBP lowering, when compared with usual care, reduces the progression of brain Aβ and tau deposition; changes in tau are correlated with neurocognitive function. 2) To determine the effects of intensive SBP lowering on CBF, central arterial stiffness, and BOLD ALFF. Hypotheses: Intensive SBP lowering reduces central arterial stiffness and increases regional CBF and BOLD ALFF; changes in CBF, arterial stiffness, and BOLD ALFF are correlated with brain Aβ and tau. 3) To determine the effects of intensive SBP lowering on brain WMH, white matter microstructural integrity, and neural network connectivity. Hypotheses: Intensive SBP lowering reduces the progression of brain WMH, improves white matter microstructural integrity and brain network connectivity which are correlated with changes in brain Aβ and tau. The new knowledge obtained will provide mechanistic insights into the relationship between hypertension, cerebrovascular function, and AD pathophysiology which is potentially important for development of multidomain strategies for dementia prevention and treatment.