Guanfacine Treatment for Prefrontal Cognitive Dysfunction in Elderly Subjects

描述（申请人提供）：在“信息时代”，当我们不断被多个同时输入淹没时，许多老年人在看似简单的任务中挣扎，例如导航银行电话树，使用遥控器看电视或dvd，使用日益重要的计算机和互联网，或在越来越复杂的道路上驾驶汽车。我们都比20年前更需要我们的“执行能力”，这对老年人来说是一个特别的挑战。认知老化的一个核心特征是由前额皮质介导的执行功能下降。这些功能包括记住刚刚发生的事情，或者记住过去的知识，并使用这些临时信息来指导行为的能力。这种表征的信息对于抑制不恰当的反应和克服先前不相关记忆的分心和干扰至关重要。前额叶的执行功能是计划、保持注意力、存储和回忆的关键，尤其是当这是一个费力的过程时。尽管前额叶执行功能障碍是衰老的一个特征和致残特征，但迄今为止还没有开发出任何治疗方法——据我们所知，甚至没有测试过——来改善这些症状。然而，二十年的动物研究表明，前额皮质的执行功能可以通过α -2肾上腺素受体激动剂得到改善。α - 2a激动剂胍法辛耐受性良好，并已证明对注意缺陷多动障碍患者有益。然而，尽管临床前研究的证据表明老年人最有可能体验到它的益处，但迄今为止，胍法辛尚未被测试其恢复老年人执行功能的能力。本研究旨在确定低剂量的α - 2a激动剂胍法辛是否可以改善健康老年人（=75岁）前额叶介导的执行功能缺陷。受试者（N=90）将随机分配接受安慰剂或胍法辛两种剂量水平中的一种：每天0.1 mg或每天0.5 mg，双盲方式持续12周。受试者将使用前额叶执行功能和识别记忆功能、临床总体印象变化和生活质量测量的综合测量来评估。该试点临床试验将为胍法辛治疗老年受试者前额叶介导的认知功能障碍的后续全面试验提供必要的初步数据。

DESCRIPTION (provided by applicant): In an "Information Age" when we are continually flooded with multiple simultaneous inputs, many elderly people struggle with seemingly simple tasks, such as navigating their bank's phone tree, using the remote to watch TV or DVDs, using the increasingly essential computer and internet, or driving the car on ever more complex roadways. We all need our "executive abilities" far more than we did even 20 years ago, and this is a particular challenge for the elderly. A core feature of cognitive aging is the decline in executive functions mediated by the prefrontal cortex. These functions include the ability to keep in mind what has just occurred, or bring to mind knowledge from the past, and use this temporary information to guide behavior. This represented information is critical for inhibiting inappropriate responses and overcoming distraction and interference from previous, now irrelevant memories. Prefrontal executive functions are key for planning, maintaining attention, and storing and recalling memories, especially when it is an effortful process. Although prefrontal executive dysfunction is a characteristic and disabling feature of aging, no treatment has been developed to date-or even tested, to our knowledge-for the amelioration of these symptoms. Yet, two decades of research in animals has demonstrated that the executive functions of the prefrontal cortex can be improved by alpha-2 adrenoreceptor agonists. The alpha-2A-agonist, guanfacine, is well-tolerated and has already demonstrated benefit in patients with attention deficit hyperactivity disorder. However, guanfacine has thus far not been tested for its ability to restore executive function in elderly adults, despite the evidence from preclinical research that the elderly are the most likely to experience its benefit. This proposal aims to determine whether low doses of the alpha-2A-agonist guanfacine can improve deficits in prefrontally-mediated executive functions in healthy elderly (=75 years) subjects. Subjects (N=90) will be randomly assigned to receive placebo or guanfacine at one of two dose levels: 0.1 mg daily, or 0.5 mg daily in double-blind fashion for 12 weeks. Subjects will be assessed using composite measures of prefrontal executive function and recognition memory function, a clinical global impression of change, and a quality of life measure. This Pilot Clinical Trial will provide essential preliminary data for a subsequent full-scale trial of guanfacine for prefrontally-mediated cognitive dysfunction in elderly subjects.