Attention and Executive Functioning in Aging and Parkisonism

描述（由申请人提供）：衰老是多种原因导致认知障碍的危险因素，认知障碍是与年龄相关的神经退行性疾病（如帕金森病（PD））的一个公认的组成部分。虽然正常衰老对记忆的影响已经在非人类灵长类动物中进行了详细的研究，但关于年龄对注意力和执行功能（日常功能的关键认知过程）的影响的研究却很少。目前还没有研究检验老年动物帕金森病非人类灵长类模型的认知状态。这一点很重要，因为衰老仍然是帕金森病的主要危险因素，我们需要更好地了解帕金森病病理对与年龄相关的神经系统变化的影响。重要的是要知道，例如，药物治疗（如尼古丁治疗）在改善年轻帕金森动物和正常老年动物的认知缺陷方面是有效的，在具有潜在不同认知和尼古丁受体谱的老年帕金森动物中仍然有效的程度。提出的研究有以下具体目的：研究年龄和慢性低剂量MPTP暴露对发展为帕金森病早期的恒河猴不同组成部分的注意和执行功能（持续注意、集合转移能力）和工作记忆（不同注意力和记忆负荷的空间工作记忆任务）的影响；具体目标2。评估亚型选择性nAChR激动剂对特异性目标1中描述的注意、执行和记忆功能障碍的潜在治疗作用；具体目标3。检查正常年龄相关和早期帕金森相关的神经化学变化和不同nAChR亚型在大脑皮层和皮层下区域的放射自显影分布。拟议的研究将首次提供与非人类灵长类动物衰老和帕金森病相关的注意力、执行功能和记忆缺陷范围的详细检查，将这些与nAChR亚型表达和分布的改变联系起来，并测试其他潜在的改善疗法。这些研究的成果将引导我们开发出针对年龄和PD相关认知功能障碍的改进疗法，并有助于将衰老和PD对认知的影响降至最低，最终提高老年人的生活质量。衰老是多种原因导致认知障碍的危险因素，认知障碍是帕金森病（PD）等与年龄相关的神经退行性疾病的一个公认的组成部分。虽然正常衰老对记忆的影响已经在非人类灵长类动物中进行了详细的研究，但关于年龄对其他日常功能的关键认知过程的影响的研究很少，例如注意力和执行功能（或潜在的治疗干预），并且没有研究检查老年动物帕金森病非人类灵长类动物模型的认知状态。这些研究的成果将引导我们开发出针对年龄和PD相关认知功能障碍的改进疗法，并有助于最大限度地减少衰老和PD对认知的影响，最终提高老年人的生活质量。

DESCRIPTION (provided by applicant): Aging is a risk factor for cognitive impairment from a variety of causes and cognitive impairment is a well-recognized component of age-related neurodegenerative diseases such as Parkinson's disease (PD). While the effects of normal aging on memory have been studied in detail in non-human primates there have been few studies of the effects of age on attention and executive functioning, critical cognitive process for everyday functioning. No studies have examined cognitive status in a non-human primate model of parkinsonism in aged animals. This is important since aging is still the primary risk factor for developing PD and we need to better understand the impact of parkinsonian pathology on a baseline of age-related neurological changes. It is important to know, for example, the extent to which pharmacotherapies (such as nicotinic therapies) that are effective in ameliorating cognitive deficits in younger parkinsonian animals and in normal aged animals remain effective in aged parkinsonian animals with potentially different cognitive and nicotinic receptor profiles. The proposed research has the following specific aims: Specific Aim 1. Examine the effects of age and chronic low dose MPTP exposure on different components of attention and executive functioning (sustained attention, set shifting ability) and working memory (spatial working memory task with different loads on attention and memory) in rhesus macaques as they develop an early stage of parkinsonism; Specific Aim 2. Assess the potential therapeutic effects of sub-type selective nAChR agonists on attention, executive and memory dysfunctions described in Specific Aim 1; Specific Aim 3. Examine normal age-related and early Parkinson-related changes in neurochemistry and autoradiographic distribution of different nAChR subtypes in cortical and subcortical brain regions. The proposed studies will be the first to provide a detailed examination of the scope of the attention, executive function and memory deficits associated with aging and parkinsonism in non-human primates, relate these to alterations in nAChR subtype expression and distribution and test other potential ameliorative therapies. Work resulting from these studies will lead us toward developing improved therapies for age and PD-related cognitive dysfunctions and should help to minimize the effects of aging and PD on cognition, ultimately leading to an improved quality of life in the older population. Aging is a risk factor for cognitive impairment from a variety of causes and cognitive impairment is a well-recognized component of age-related neurodegenerative diseases such as Parkinson's disease (PD). While the effects of normal aging on memory have been studied in detail in non-human primates there have been few studies of the effects of age on other critical cognitive process for everyday functioning such as attention and executive functioning (or on potential therapeutic interventions) and no studies have examined cognitive status in a non-human primate model of parkinsonism in aged animals. Work resulting from the proposed studies will lead us toward developing improved therapies for age and PD-related cognitive dysfunctions and should help to minimize the effects of aging and PD on cognition, ultimately leading to an improved quality of life in the older population.