Cognitive and Cerebrovascular Sequelae of Hypertension

高血压的认知和脑血管后遗症

• 批准号: 6781769
• 负责人: JOHN RICHARD JENNINGS
• 金额: $ 50.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781769
• 关键词: acetazolamide; aging; atenolol; behavioral /social science research tag; brain circulation; cardiovascular disorder chemotherapy; cerebrovascular disorders; chronic disease /disorder; clinical trials; cognition disorders; essential hypertension; hemodynamics; human middle age (35-64); human subject; human therapy evaluation; learning; lisinopril; longitudinal human study; magnetic resonance imaging; memory; neuropsychological tests; neuropsychology; pathologic process; patient oriented research; positron emission tomography; statistics /biometry

DESCRIPTION (provided by applicant): Chronic diseases, which increase in prevalence with age, impair intellectual functioning. We and others have found that patients with essential hypertension have impaired performance on neuropsychological tests relative to age-matched controls. At the initiation of our project, the mechanism by which hypertension impaired intellectual function was unknown. We hypothesized that the morphological changes (vascular remodeling) associated with hypertension might interfere with regional cerebral blood flow (rCBF) responses induced by information processing. We have now shown with Positron Emission Tomography (PET) that hypertension impairs rCBF, altering both flow volume and the patterning of flow within the brain. The differences in flow volume are specific to hypertensives performing poorly on a test of working memory. Overall, hypertensive performing mnemonic tasks show a left lateralized increase in rCBF in prefrontal, and perhaps, posterior parietal areas that exceeds that of normotensives. As a result of this difference, hypertensives process the mnemonic task bilaterally; while normotensives tend to show a dominant right hemisphere processing. During the current project, we have also tested a second hypothesis that other vascular pathology might contribute to the cognitive impairment of hypertensives, either atherosclerotic changes assessed indirectly from thickening of the carotid artery wall and/or white matter lesions in the brain detected by magnetic resonance imaging (MRI). Initial data analyses, however, fail to provide strong support for this second hypothesis. We now propose to test our vascular hypothesis of the source of cognitive impairments associated with hypertension. We suggest that reversing both the heightened blood pressure and vascular remodeling of hypertension will also normalize both rCBF and cognitive performance. Pharmacological advances in the treatment of hypertension have now shown that angiotension converting enyzme (ACE) inhibitors and beta-blockers differ in their influence on the vasculature. Both medications reduce blood pressure, but ACE inhibitors also reduce medial wall thickness and restore the sensitivity of the vascular endothelium to nitric oxide. This permits us to test our vascular model. We hypothesize that an ACE inhibitor, lisinopril, will normalize rCBF and cognitive function relative to the actions of a beta-blocker, atenolol. We further suggest that this effect will be mediated by lisinopril's action on the vasculature as assessed peripherally via a brachial artery flow mediated vasodilation probe and centrally via testing for cerebrovascular reserve with the administration of acetazolamide (Diainox). Based on the literature, a one-year treatment period will be required to adequately test our hypothesis. Should we be successful, our project will have advanced considerably toward our ultimate goal of identifying mechanisms for how diseases of aging influence intellectual functioning. Successful completion will clarify a) how one major disease of aging reduces intellectual functioning and b) permit a rational choice of clinical regimen to treat this disease while minimizing neuropsychological side effects.

描述（申请人提供）：慢性疾病，增加 患病率随着年龄的增长而损害智力功能。我们和其他人发现 基本高血压患者在 与年龄匹配的对照相关的神经心理学测试。启动 我们的项目，高血压障碍智力功能的机制 是未知的。我们假设形态学变化（血管变化 与高血压相关的重塑）可能会干扰区域大脑 信息处理引起的血流（RCBF）反应。我们现在有 用正电子发射断层扫描（PET）显示，高血压会损害RCBF， 改变了大脑内流量和流动的模式。这 流量体积的差异特异于高血压在A上的表现不佳 工作记忆测试。总体而言，高血压性能的助记符任务显示 前额叶的RCBF左侧增加，也许是后部 超过正常敏化的顶叶区域。结果 差异，高血压双侧处理助理任务；尽管 正常光敏剂倾向于显示右半球的主要处理。在 当前的项目，我们还检验了第二个假设，即其他血管 病理可能会导致高血压的认知障碍 颈动脉增厚间接评估了动脉粥样硬化变化 通过磁性检测到的大脑中的动脉壁和/或白质病变 共振成像（MRI）。但是，初始数据分析无法提供强大的 支持第二个假设。我们现在建议测试我们的血管 与高血压相关的认知障碍来源的假设。 我们建议逆转升高的血压和血管 高血压的重塑还将使RCBF和认知能力归一化 表现。高血压治疗的药理学进步 表明血管敏感转化Enyzme（ACE）抑制剂和β受体阻滞剂 它们对脉管系统的影响不同。两种药物都减少了血液 压力，但ACE抑制剂也减少了内侧壁厚并恢复 血管内皮对一氧化氮的敏感性。这允许我们 测试我们的血管模型。我们假设ACE抑制剂Lisinopril将 相对于A的动作，将RCBF和认知功能归一化 Beta-Blocker，Atenolol。我们进一步建议，这种效果将由 Lisinopril对脉管系统的作用是通过肱骨外周评估的 动脉流介导的血管舒张探针和通过测试中心 脑血管储备和乙酰唑胺（DIAINOX）的给药。 根据文献，将需要一年的治疗期 充分检验我们的假设。如果我们成功，我们的项目将有 朝着我们确定机制的最终目标的大幅度提高 衰老疾病如何影响智力功能。成功完成 将澄清a）一种主要的衰老疾病如何降低智力功能 b）允许合理选择临床方案来治疗这种疾病 最小化神经心理学的副作用。