Guanfacine Treatment for Prefrontal Cognitive Dysfunction in Elderly Subjects

描述(申请人提供)：在信息时代，我们不断地被多个同步输入淹没，许多老年人在看似简单的任务中苦苦挣扎，比如浏览银行的电话树，用遥控器看电视或DVD，使用日益重要的计算机和互联网，或者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叶皮质调节的执行功能下降。这些功能包括记住刚刚发生的事情，或者让人想起过去的知识，并使用这些临时信息来指导行为。这种被代表的信息对于抑制不恰当的反应和克服来自以前的、现在无关的记忆的分心和干扰至关重要。前额叶执行功能是计划、保持注意力、储存和回忆记忆的关键，特别是当这是一个费力的过程时。虽然前额叶执行功能障碍是衰老的一个特征和致残特征，但到目前为止还没有开发出--甚至据我们所知--改善这些症状的治疗方法。然而，二十年的动物研究表明，阿尔法-2肾上腺素受体激动剂可以改善前额叶皮质的执行功能。α-2a激动剂，鸟嘌呤，耐受性良好，已经显示出对注意缺陷多动障碍患者的益处。然而，尽管来自临床前研究的证据表明，老年人最有可能体验到它的好处，但到目前为止，鸟嘌呤还没有接受过测试，看看它是否有能力恢复老年人的执行功能。这项建议旨在确定小剂量的α-2A激动剂瓜那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)将被随机分配接受两种剂量水平中的一种：每天0.1毫克，或以双盲方式每天接受0.5毫克，为期12周。受试者将使用前额叶执行功能和再认记忆功能、临床总体变化印象和生活质量测量的综合测量进行评估。这项先导性临床试验将为随后的用于治疗前额叶介导的老年认知功能障碍的金刚法新的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.