Hypertension angiotensin receptor blockers and cognition: effects and mechanism

描述(申请人提供)：即使在没有痴呆的情况下，高血压也与认知障碍有关。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，还没有针对执行性轻度认知障碍的特定治疗方法，这种认知障碍与高血压的不良结局有关。在K23奖项的支持下，PI最近完成了一项预备性试点研究(n=47)，以测试血管紧张素受体阻滞剂坎地沙坦与氢氯噻嗪和赖诺普利在高血压和以执行功能障碍为特征的轻度认知障碍患者中的可行性、安全性和有效剂量。我们最近在《内科医学档案》上发表的初步分析表明，坎地沙坦在维持执行功能方面优于其他降压药，与血压无关。坎地沙坦还与脑血流速度增加有关，仅在基线时血流速度低的患者(n=23)才达到显著水平。基于这些数据，我们假设进一步测试血管紧张素受体阻滞剂对认知功能的影响，对160名高血压患者和赖诺普利患者进行了为期一年的坎地沙坦和赖诺普利的双盲随机主动对照试验，并有证据表明执行领域存在轻度认知障碍。该方案的具体目的是观察坎地沙坦对执行功能下降的影响，以及对脑血流灌注、脑血管储备和微血管损伤的影响。我们还旨在确定与血管结构和功能相关的潜在机制，坎地沙坦可能通过这些机制影响认知和脑血管结果。参与者将从大洛杉矶地区招募，并在南加州大学进行评估。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后12个月进行。在基线和治疗12个月后，将进行神经成像，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的血管性脑损伤的潜在治疗作用。该项目还将提高我们对这类抗高血压药物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.