Hypertension angiotensin receptor blockers and cognition: effects and mechanism

描述（由申请人提供）：即使没有痴呆，高血压也与认知障碍相关。这些与血管相关的轻度认知障碍未被发现，通常以执行功能障碍为特征。到目前为止，没有具体的治疗可用于执行轻度认知障碍，这是与高血压的不良结局。PI最近在K23奖的支持下完成了一项预备性试点研究（n=47），以测试坎地沙坦（一种血管紧张素受体阻滞剂）与氢氯噻嗪和赖诺普利相比在高血压和轻度认知障碍（以执行功能障碍为特征）患者中的可行性、安全性和效应量。我们的初步分析最近被接受发表在《内科学档案》上，表明坎地沙坦在保护执行功能方面上级其他降压药，与血压无关。坎地沙坦还与脑血流速度增加相关，仅在基线时血流速度较低的患者中达到显著性（n=23）。基于这些数据，我们进行了一项为期1年的坎地沙坦与赖诺普利双盲随机活性对照试验，在160名高血压患者中进一步测试血管紧张素受体阻滞剂对认知功能的影响，并在执行领域有轻度认知障碍的证据。本提案的具体目的是研究坎地沙坦对执行功能下降以及对脑灌注、脑血管储备和微血管脑损伤变化的影响。我们还旨在确定坎地沙坦可能影响认知和脑血管结局的与血管结构和功能相关的潜在潜在机制。参与者将从大洛杉矶地区招募，并在南加州大学进行评估。将在基线和治疗后12个月进行评估执行功能和其他认知领域的认知测试。将在基线和治疗12个月后进行神经影像学检查，包括灌注（连续动脉自旋标记）和微结构（扩散张量成像）、颈动脉超声（颈动脉内膜中层厚度）以及内皮和血管炎症标志物。这项试验将进一步阐明血管紧张素受体阻滞剂对执行功能障碍和相关血管性脑损伤的潜在治疗作用。这个项目也将提高我们对这类抗高血压药物的可能作用机制的理解。

DESCRIPTION (provided by applicant): Hypertension is associated with cognitive impairment even in the absence of dementia. These vascular-related mild cognitive impairments are undetected and are commonly characterized by executive dysfunction. To date, no specific treatment is available for executive mild cognitive impairment which is associated with poor outcomes in hypertension. The PI has recently completed, with support from a K23 award, a preparatory pilot study (n=47) to test the feasibility, safety and effect size of candesartan, an angiotensin receptor blocker, compared to hydrochlorothiazide and lisinopril, in individuals with hypertension and mild cognitive impairment characterized by executive dysfunction. Our preliminary analysis which was recently accepted for publication in the Archives of Internal Medicine, suggests that, independent of blood pressure, candesartan is superior to other antihypertensives in preserving executive function. Candesartan was also associated with an increase in cerebral blood flow velocity that only reached significance in those with low flow velocity at baseline (n=23). We hypothesized based on these data to further test the effect of angiotensin receptor blockers on cognitive function by conducting a 1-year double blind randomized active-control trial of candesartan vs. lisinopril in 160 individuals with hypertension and evidence of mild cognitive impairment in the executive domain. The specific aims of this proposal are to investigate the effects of candesartan on executive function decline and on change in cerebral perfusion, cerebrovascular reserve and microvascular brain injury. We also aim at Identifying potential underlying mechanisms related to vascular structure and function by which candesartan may affect the cognitive and cerebrovascular outcomes. Participants will be recruited from the greater Los Angeles Area and evaluated at the University of Southern California. Cognitive tests that assess executive function and other cognitive domains will be administered at baseline and 12 months after treatment. Neuroimaging which includes perfusion (continuous arterial spin labeling) and micro-structure (diffusion tensor imaging), carotid ultrasound (carotid intima-media thickness), and endothelial and vascular inflammatory markers will be performed at baseline and after 12 months of treatment. This trial will shed more light onto the potential therapeutic effects of angiotensin receptor blockers on executive dysfunction and related vascular brain injury. This project will also improve our understanding of the possible mechanisms of action of this class of antihypertensives.