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: 10558579
• 负责人: David H Farb
• 金额: $ 80.27万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558579
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Angiotensin II Type 1 Receptor Blockers; Attenuated; Blood - brain barrier anatomy; Blood Pressure; Blood brain barrier dysfunction; Cardiovascular system; Cerebral small vessel disease; Cerebrum; Clinical; Cognition; Data; Dementia; Development; Electrophysiology (science); Event; Exhibits; Female; Functional disorder; Goals; Gonadal Hormones; Hemorrhage; Hippocampus; Hypertension; Impaired cognition; Incidence; Link; Maintenance; Modeling; Neurocognitive; Neuronal Dysfunction; Neurons; Neurosciences; Outcome; Ovariectomy; Play; Postmenopause; Prevalence; Public Health; Rattus; Receptor, Angiotensin, Type 1; Research; Risk Factors; Rodent; Role; Source; Specialist; Sprague-Dawley Rats; Testing; Vascular Cognitive Impairment; Woman; age related; aged; antagonist; 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; neuroprotection; neuroregulation; new therapeutic target; normal aging; novel; paraventricular nucleus; sex; vascular injury

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.

抽象的 高血压是脑小血管疾病发展的关键危险因素，脑小血管疾病是脑小血管疾病的首要来源。 血管性认知障碍是继阿尔茨海默病之后导致痴呆的第二常见原因。 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性认知障碍的发展。尽管 血管紧张素 II 1 型受体拮抗剂是治疗高血压的一线疗法 被证明可以改善神经认知功能。鉴于美国每年因痴呆症造成的损失预计 到 2040 年，美国 20-44 岁成年人的高血压患病率将增加一倍，从 46% 上升到 78% 以上。 65岁以上的成年人，绝经后高血压发病率急剧增加 关键的公共卫生需要更好地了解性别、年龄依赖性之间的机制联系 高血压和血管性认知障碍。该应用程序将测试正常的全局假设 衰老会引起性别依赖性高血压，从而导致中枢微血管损伤和神经炎症 引起血管性认知障碍，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、8 和 16 个月大的雄性和雌性 Sprague-Dawley 大鼠（模型）中进行 正常老化）。以下具体目标将检验该假设： 具体目标 1：下丘脑 PVN 血液 脑屏障功能障碍和神经炎症通过可逆性机制导致年龄依赖性高血压 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 诱发海马微血管损伤和神经回路功能障碍导致血管性认知障碍 通过可逆的性别依赖性血管紧张素 II 1 型受体机制。我们的创新方法是直接 与解决阿尔茨海默病及其相关痴呆症的 NIA 战略目标保持一致，并设计 为性别和年龄依赖性高血压的基本机制提供新的见解 驱动的血管性认知障碍，完全符合 PAR-19-070 和 NOT-AG-20-038 的意图。具体的 目标 1 将确定下丘脑 PVN 血脑屏障功能障碍和神经炎症会导致 年龄依赖性高血压的发展，通过可逆性机制导致血管性认知障碍 性别依赖性血管紧张素 II 1 型受体机制。具体目标 2 将确定年龄依赖性 高血压诱发海马微血管损伤，神经回路功能障碍驱动血管认知 通过可逆的性别依赖性血管紧张素 II 1 型受体机制造成损害。我们的创新 该方法将直接研究事件的性别依赖性机制后遗症和潜在的神经 PVN 和海马体功能障碍与年龄有关，并且可能是其原因之一 依赖性高血压驱动的血管性认知障碍。