Guanfacine Treatment for Prefrontal Cognitive Dysfunction in Elderly Subjects

描述（由申请人提供）：在一个“信息时代”，当我们不断地被多个同时输入淹没时，许多老年人正在努力完成看似简单的任务，例如在银行的电话树中导航，使用遥控器看电视或DVD，使用越来越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层介导的执行功能的下降。这些功能包括记住刚刚发生的事情的能力，或者记住过去的知识，并使用这些临时信息来指导行为。这些表征的信息对于抑制不适当的反应，克服以前的干扰和干扰至关重要，现在无关的记忆。前额叶执行功能是计划，保持注意力，存储和回忆记忆的关键，特别是当它是一个努力的过程时。虽然前额执行功能障碍是衰老的一个特征和致残特征，但据我们所知，迄今为止还没有开发出或测试过改善这些症状的治疗方法。然而，20年的动物研究表明，前额叶皮层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，已经证明对注意缺陷多动障碍患者有益。然而，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，尽管临床前研究的证据表明老年人最有可能体验到其益处。该提案旨在确定低剂量的α-2A激动剂胍法辛是否可以改善健康老年（≥ 75岁）受试者的前额叶介导的执行功能缺陷。受试者（N=90）将被随机分配接受安慰剂或胍法辛，两种剂量水平之一：0.1 mg每日或0.5 mg每日，以双盲方式持续12周。将使用前额叶执行功能和识别记忆功能的复合指标、临床总体变化印象和生活质量指标对受试者进行评估。这项初步临床试验将为后续的胍法辛治疗老年受试者前额叶介导的认知功能障碍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.