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

收缩压强化治疗对老年人脑灌注、淀粉样蛋白和 Tau 蛋白的影响（IPAT 研究）

• 批准号: 10425191
• 负责人: WANPEN VONGPATANASIN
• 金额: $ 236.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425191
• 关键词: Abeta clearance; Adult; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Biological; Biological Process; Blood Pressure; Brain; Cardiovascular Diseases; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Dementia; Deposition; Development; Elderly; Enrollment; Etiology; Family history of; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Healthcare; Hypertension; Impaired cognition; Incidence; Injury; Intervention; Isolated systolic hypertension; Knowledge; Magnetic Resonance Imaging; Measures; Memory; Meta-Analysis; National Institute on Aging; Neurocognitive; Outcome; Participant; Pathogenesis; Pathology; Perfusion; Pharmacologic Substance; Positron-Emission Tomography; Prevention; Randomized; Regulation; Research; Rest; Risk; Risk Factors; Rodent; Role; Signal Transduction; Societies; Stroke; White Matter Hyperintensity; abeta accumulation; aged; arm; arterial stiffness; base; blood oxygen level dependent; blood pressure medication; blood-based biomarker; cerebrovascular; dementia risk; effective therapy; glymphatic system; high risk; hypertension treatment; improved; indexing; insight; middle age; neural network; neuroimaging; prevent; tau Proteins; treatment as usual; white matter; β-amyloid burden

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.

老年高血压强化治疗对脑血流灌注、淀粉样蛋白及Tau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学结构 Aβ和tau蛋白的表达。同样，脑血管对AD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; 65岁或以上的成年人患有高血压。SPRINT试验表明，高血压的强化治疗 降低认知障碍或痴呆的风险。然而，其潜在机制尚不清楚。 高血压和相关的动脉硬化损害局部脑血流量（CBF），减少 脑白色物质的完整性，并通过脑胶质淋巴系统影响脑淀粉样蛋白和tau蛋白的清除。我们 研究还表明，高血压和中央动脉僵硬度与大脑 用PET测量Aβ负荷，血氧水平的低频波动幅度- 在老年人中，用rs-fMRI（BOLD ALFF）测量的依赖信号与脑淀粉样蛋白负荷呈负相关。 成年人，表明其在脑Aβ调节中的作用。本项目的首要目标是确定 是否将收缩压（SBP）强化降低至<120 mmHg的目标，与 <140 mmHg，降低老年人痴呆症高危人群的大脑淀粉样蛋白和tau蛋白。 此外，我们将确定血压降低对CBF、动脉僵硬度、BOLD ALFF、白色 物质高强度（WMH），大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蛋白的关系。我们将招募180名60至80岁的老年人， 患有高血压（SBP≥130 mmHg）、痴呆FH和/或主观记忆主诉的患者。 参与者将被随机分配到强化治疗组（SBP<120 mmHg）或常规治疗组（SBP<140 mmHg） 两组，随访2年，以实现以下具体目标：1）确定 强化SBP降低对脑淀粉样蛋白、tau蛋白和神经认知功能的影响。假设：强化SBP 与常规护理相比，降低剂量可减少脑Aβ和tau沉积的进展; tau与神经认知功能相关。2)为了确定强化降低SBP对CBF的影响， 中心动脉僵硬和BOLD ALFF。假设：强化SBP降低降低了中心动脉 僵硬，并增加局部CBF和BOLD ALFF; CBF，动脉僵硬度和BOLD ALFF的变化是 与脑Aβ和tau蛋白相关。3)为了确定强化降低SBP对脑WMH的影响，白色 物质微观结构完整性和神经网络连接性。假设：强化SBP降低 脑WMH的进展，改善了白色物质微结构的完整性和脑网络的连通性 这与脑Aβ和tau蛋白的变化有关。获得的新知识将提供机械的 深入了解高血压、脑血管功能和AD病理生理学之间的关系， 对痴呆症预防和治疗的多领域策略的发展具有潜在的重要意义。