Attention and Executive Functioning in Aging and Parkisonism

衰老和帕金森病中的注意力和执行功能

• 批准号: 7372596
• 负责人: JAY S SCHNEIDER
• 金额: $ 49.61万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372596
• 关键词: Acetylcholine; Adrenergic Agents; Affect; Age; Aging; Agonist; Anatomy; Animals; Attention; Behavioral; Biological Models; Brain region; Cholinergic Agents; Chronic; Class; Clinical; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Disease; Doctor of Medicine; Dopamine; Dose; Economics; Functional disorder; Glutamates; Health; Human; Impaired cognition; Intervention; Lead; Macaca mulatta; Memory; Memory impairment; Mental disorders; Modeling; Molecular Profiling; Monkeys; Nature; Neurodegenerative Disorders; Neurologic; Neurons; Neurotoxins; Neurotransmitters; Nicotine; Nicotinic Agents; Nicotinic Receptors; Norepinephrine; Numbers; Older Population; Opioid Peptide; Parkinson Disease; Parkinsonian Disorders; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Process; Quality of life; Range; Research; Resources; Risk Factors; Serotonin; Short-Term Memory; Staging; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Translational Research; Treatment Efficacy; Work; acetylcholine receptor agonist; age effect; age related; aged; aging population; brain behavior; cholinergic; clinically significant; cognitive function; drug discovery; drug efficacy; early onset; endogenous opioids; executive function; gamma-Aminobutyric Acid; improved; insight; mature animal; neurobehavioral; neurochemistry; nonhuman primate; normal aging; older patient; pathological aging; receptor; receptor expression; relating to nervous system; response; restorative treatment; young adult

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.

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。虽然在非人类灵长类动物中详细研究了正常衰老对记忆的影响，但很少有关于年龄对注意力和执行功能（日常功能的关键认知过程）影响的研究。没有研究检查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，因为衰老仍然是发生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学对与年龄相关的神经系统变化基线的影响。例如，重要的是要知道，对于改善年轻帕金森病动物和正常老年动物的认知缺陷有效的药物疗法（例如烟碱疗法）在多大程度上对具有潜在不同认知和烟碱受体谱的老年帕金森病动物仍然有效。拟议的研究有以下具体目标： 具体目标 1. 检验年龄和长期低剂量 MPTP 暴露对注意力和执行功能（持续注意力、设定转移能力）和工作记忆（不同任务的空间工作记忆任务）不同组成部分的影响。当恒河猴患上帕金森病的早期阶段时，它们会增加注意力和记忆力；具体目标 2. 评估亚型选择性 nAChR 激动剂对具体目标 1 中描述的注意力、执行和记忆功能障碍的潜在治疗效果；具体目标 3. 检查皮质和皮质下脑区域不同 nAChR 亚型的神经化学和放射自显影分布中与年龄相关的正常变化和与早期帕金森相关的变化。拟议的研究将是第一个详细检查非人类灵长类动物中与衰老和帕金森病相关的注意力、执行功能和记忆缺陷的范围，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方法疗法。这些研究的成果将引导我们开发针对年龄和帕金森病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帕金森病对认知的影响，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。虽然已经在非人类灵长类动物中详细研究了正常衰老对记忆的影响，但很少有人研究年龄对日常功能的其他关键认知过程的影响，例如注意力和执行功能（或潜在的治疗干预措施）和没有研究检查老年动物帕金森病非人类灵长类模型的认知状态。拟议研究的结果将引导我们开发针对年龄和帕金森病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帕金森病对认知的影响，最终提高老年人的生活质量。