Age-related Hypertension and Vascular Cognitive Impairment

年龄相关性高血压和血管性认知障碍

• 批准号: 10375761
• 负责人: David H Farb
• 金额: $ 83.55万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375761
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Angiotensin II Type 1 Receptor Blockers; Attenuated; Blood - brain barrier anatomy; Blood Pressure; Cardiovascular system; Cerebral small vessel disease; Cerebrum; Clinical; Cognition; Data; Dementia; Development; Electrophysiology (science); Event; Exhibits; Female; Functional disorder; Goals; Gonadal Hormones; Hippocampus (Brain); Hypertension; Impaired cognition; Incidence; Injury; Life; Link; Maintenance; Modeling; Neurocognitive; Neuronal Dysfunction; Neurons; Neurosciences; Outcome; Ovariectomy; Play; Postmenopause; Prevalence; Public Health; Rat-1; Rattus; Receptor, Angiotensin, Type 1; Research; Risk Factors; Rodent; Role; Source; Specialist; Sprague-Dawley Rats; Testing; Vascular Cognitive Impairment; Woman; age related; aged; blood pressure reduction; blood pressure regulation; cognitive function; cost; design; female sex hormone; healthy aging; hypertensive; improved; innovation; insight; male; mild cognitive impairment; multidisciplinary; neural circuit; neuroinflammation; neuroregulation; new therapeutic target; normal aging; novel; paraventricular nucleus; sex

ABSTRACT Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment which is the second most common cause of dementia after Alzheimer’s disease. There is increasing evidence that blood brain barrier dysfunction and neuroinflammation play a pivotal role in the pathophysiology of hypertension and contribute to the development of vascular cognitive impairment. While Angiotensin II Type 1 receptor antagonists are first line therapy to treat hypertension they have recently been demonstrated to improve neurocognitive function. Given the annual cost of dementia in the US is expected to double by 2040, the prevalence of hypertension rises from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65, and that hypertension incidence increases dramatically post-menopause there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension and vascular cognitive impairment. This application will test the global hypothesis that normal aging evokes sex-dependent hypertension that drives central microvascular injury and neuroinflammation to cause vascular cognitive impairment which can be ameliorated by Angiotensin II Type 1 receptor antagonism. Our Aims will be conducted in male and female 3-, 8-, and 16-month-old Sprague-Dawley rats (model of normal aging). The following Specific Aims will test this hypothesis: Specific Aim 1: Hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to age-dependent hypertension via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2: Age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach is directly aligned with NIA Stratetgic Goals that address Alzheimer's disease and its related dementias and is designed to provide novel insights into the basic mechanisms contributing to sex- and age-dependent hypertension- driven vascular cognitive impairment and fully meets the intent of PAR-19-070 and NOT-AG-20-038. Specific Aim 1 will establish that hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to the development of age-dependent hypertension, which drives vascular cognitive impairment, via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2 will establish that age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach will directly investigate the sex dependent mechanistic sequelae of events and underlying neural dysfunction in both the PVN and hippocampus that is associated with, and perhaps contributing to, age- dependent hypertension-driven vascular cognitive impairment.

摘要 高血压是发展脑部小血管疾病的关键危险因素，是脑血管疾病的最主要来源 血管认知障碍是继阿尔茨海默病之后导致痴呆症的第二大常见原因。 越来越多的证据表明，血脑屏障功能障碍和神经炎症在 高血压的病理生理学，并有助于血管认知功能障碍的发展。而当 血管紧张素II 1型受体拮抗剂是治疗高血压的一线药物，最近它们被 证明能改善神经认知功能。鉴于美国每年痴呆症的成本，预计 到2040年，高血压患病率将从20-44岁的美国成年人的46%上升到美国的78%。 65岁以上的成年人，而且绝经后高血压的发病率急剧增加 关键的公共卫生需要更多地了解性别、年龄相关性之间的机械联系(S) 高血压和血管认知障碍。这个应用程序将测试全局假设，即正常 衰老引起性别依赖性高血压，导致中枢微血管损伤和神经炎症 引起血管认知障碍，可通过血管紧张素II 1型受体拮抗剂改善。 我们的目标将在3个月、8个月和16个月大的雄性和雌性SD大鼠(模型 正常衰老)。以下特定目标将验证这一假设：特定目标1：下丘脑室旁核血液 脑屏障功能障碍和神经炎症通过可逆性高血压促进年龄依赖性高血压 性别依赖性血管紧张素II 1型受体机制。具体目标2：年龄依赖性高血压 诱发的海马微血管损伤和神经回路功能障碍导致血管性认知功能障碍 通过可逆的性别依赖的血管紧张素II 1型受体机制。我们的创新方法直接 与NIA应对阿尔茨海默病及其相关痴呆的战略目标保持一致，并设计 为了对性别和年龄依赖性高血压的基本机制提供新的见解- 导致血管认知障碍，完全符合PAR-19-070和NOT-AG-20-038的意图。特定的 目的1将确定下丘脑室旁核血脑屏障功能障碍和神经炎症有助于 年龄依赖性高血压的发展，它通过可逆的 性别依赖性血管紧张素II 1型受体机制。具体目标2将确立与年龄有关 高血压引起的海马微血管损伤和神经回路功能障碍推动血管认知 通过可逆性依赖的血管紧张素II 1型受体机制造成的损伤。我们的创新 方法将直接研究性别依赖的事件和潜在神经的机械性后遗症 下丘脑室旁核和海马体的功能障碍与年龄有关，可能与年龄有关- 依赖型高血压导致的血管认知障碍。