Cognition in Parkinson's Disease

帕金森病的认知

• 批准号: 8195997
• 负责人: DEBORAH Lynn HARRINGTON
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195997
• 关键词: Adult; Affect; Afghanistan; Alzheimer' s Disease; Attention; Behavior; Biological Availability; Brain; Brain region; Brain-Derived Neurotrophic Factor; Catechols; Cognition; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; Craniocerebral Trauma; Data; Decision Making; Dementia; Dependence; Development; Disease; Dopamine; Dopamine Agonists; Early treatment; Elderly; Environment; Enzymes; Freezing; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Healthcare Systems; Image; Impaired cognition; Impairment; Incidence; Individual; Individual Differences; Iraq; Knowledge; Lead; Learning; Link; Maintenance; Mediating; Modality; Modeling; Monitor; Motor; Movement; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neuroprotective Agents; Parkinson Disease; Participant; Patients; Pattern; Perception; Performance; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Population; Predisposition; Prefrontal Cortex; Prevalence; Process; Reporting; Research; Role; Short-Term Memory; Signal Transduction; Staging; Stimulus; Symptoms; Synapses; Testing; Time; Transferase; Update; Variant; Veterans; Walking; aging population; base; cognitive control; cognitive function; disability; distraction; drug development; experience; flexibility; improved; insight; interest; neural circuit; neural patterning; neurobehavioral; neurophysiology; normal aging; prevent; programs; public health relevance; relating to nervous system; research study; response; theories; transmission process; treatment response; volunteer

DESCRIPTION (provided by applicant): The neural bases of cognitive symptoms in Parkinson's disease (PD) are not well understood, nor are the effects of dopamine (DA) therapy, which can be neutral, beneficial, or detrimental. Cognitive symptoms in PD can be related to the distinction between cognitive stability and flexibility mechanisms, which are thought to depend on the opposing roles of the prefrontal cortex (PFC) and striatum, respectively. Cognitive stability is a component of working memory that involves encoding and maintenance of representations in the face of distraction. Cognitive flexibility involves updating and integrating information in working memory. Although it is unclear whether DA therapy improves stability and flexibility deficits in PD, the neural substrates of these mechanisms are linked to the expression of genes that are related to baseline levels of DA in the brain and cognitive proficiency. Thus, the neurobehavioral response to DA therapy in PD may depend on the expression of these genes. This project will use fMRI to identify disease-related patterns of activity in PD that disrupt the stability and flexibility of timing, which is a predictive process that also depends on DA and is vital for cognition and movement. Objectives 1 and 2 will identify the neural bases of deficits in timing stability and flexibility in PD. Objective 3 will determine the effect of DA therapy on timing stability and flexibility and their neural substrates. Objective 4 will determine if COMT val158met and BDNF val66met expression distinguish the response of the PFC (stability) and striatum (flexibility) to DA therapy in PD. In each experiment, 24 healthy adults and 24 individuals with PD will be tested as they undergo fMRI while performing tasks that probe for stability (Experiment 1) and flexibility (Experiment 2) effects on temporal cognition. PD volunteers will be tested once after they stop their DA therapy overnight so that they are in a practical 'off" state, and once after taking their normal DA therapy to evaluate the effect of medication on neurobehavioral functioning. It is predicted that disease- related patterns of PFC and striatal activation in PD will differ during probes for timing stability and flexibility. Neurobehavioral responses to DA therapy are expected to depend on the expression of COMT val158met in the PFC and BDNF val66met in the striatum. This research is expected to identify the neural markers for key components of cognitive dysfunction in PD. Insight into the influence of genetic factors on neurobehavioral responses to DA therapy is crucial for elucidating complex physiological and pharmacotherapy interactions that could guide individualized treatments and influence drug development. PUBLIC HEALTH RELEVANCE: This proposal responds to the CSR&D Program solicitation for research in PD. The prevalence of PD is 1% to 3% in adults over the age of 65, making it second only to Alzheimer's disease as a neurodegenerative disorder. The incidence in the veteran population is likely to increase further due to head injuries in veterans returning from Afghanistan and Iraq, as people who experience neurotrauma are four to eight times more likely to develop idiopathic PD. As such, with a larger proportion of the population aging, the numbers of people with PD can be expected to increase substantially by the year 2020, placing even greater demands on the VA health care system. The present proposal's focus on cognitive disabilities in PD is therefore timely and long overdue, as treatment approaches for cognitive dysfunction in PD are largely overlooked, despite an incidence of about 50% early in the disease. Many people with PD eventually develop dementia, which is three to four times more prevalent than in normal aging. As such, it is vital to understand cognitive disabilities in PD, their neuronal bases, and their responsiveness to DA therapy, which remains the main pharmacotherapeutic approach. The role that genetic factors play in determining neural-cognitive responses to DA therapy is also critical for understanding the considerable individual differences in the effect of DA treatment on cognitive dysfunction. This knowledge could promote more optimal, individualized treatments and drive the development of new medication treatments.

描述（由申请人提供）： 帕金森氏病（PD）中认知症状的神经碱基尚不清楚，多巴胺（DA）疗法的影响也可能是中性，有益或有害的。 PD中的认知症状可能与认知稳定性和柔韧性机制之间的区别有关，这被认为取决于前额叶皮层（PFC）和纹状体的相对作用。认知稳定性是工作记忆的一个组成部分，涉及面对分心的表示和维护。认知灵活性涉及在工作记忆中更新和集成信息。尽管尚不清楚DA疗法是否改善了PD的稳定性和柔韧性缺陷，但这些机制的神经底物与与大脑中DA基线水平相关的基因表达和认知能力相关的基因表达有联系。因此，对PD中DA治疗的神经行为反应可能取决于这些基因的表达。该项目将使用fMRI来确定PD中与疾病相关的活动模式，这破坏了计时的稳定性和灵活性，这是一个预测过程，也取决于DA，对于认知和运动至关重要。目标1和2将在PD中确定定时稳定性和灵活性中缺陷的神经底部。目标3将确定DA疗法对时间稳定性和灵活性及其神经底物的影响。目标4将确定COMT Val158MET和BDNF Val66met表达是否区分PFC（稳定性）和纹状体（柔韧性）对PD治疗的反应。在每个实验中，将在执行探测稳定性（实验1）和灵活性（实验2）对时间认知的任务的同时，将对24名健康成年人和24名患有PD的人进行测试。 PD volunteers will be tested once after they stop their DA therapy overnight so that they are in a practical 'off" state, and once after taking their normal DA therapy to evaluate the effect of medication on neurobehavioral functioning. It is predicted that disease- related patterns of PFC and striatal activation in PD will differ during probes for timing stability and flexibility. Neurobehavioral responses to DA therapy are expected to depend on纹状体中PFC和BDNF Val66met中COMT Val158met的表达有望确定对PD的认知功能障碍的关键组成部分。 公共卫生相关性： 该提案对PD研究的CSR＆D计划征集响应。在65岁以上的成年人中，PD的患病率为1％至3％，使其仅次于阿尔茨海默氏病作为神经退行性疾病。由于从阿富汗和伊拉克返回的退伍军人的头部受伤，退伍军人人口的发病率可能会进一步增加，因为经历神经病的人的发病率是发展特发性PD的四到八倍。因此，随着人口衰老的比例，PD的人数预计到2020年可以大幅增加，对VA医疗保健系统的需求更大。因此，本提案对PD的认知障碍的关注是及时且早已逾期的，因为尽管疾病早期发生了大约50％的PD治疗方法，但PD中的认知功能障碍的治疗方法在很大程度上被忽略了。许多患有PD的人最终发展出痴呆症，这是正常衰老的三到四倍。因此，了解PD中的认知障碍，其神经元碱以及对DA疗法的反应至关重要，这仍然是主要的药物治疗方法。遗传因素在确定对DA治疗的神经认知反应中所起的作用对于理解DA治疗对认知功能障碍的影响的个体差异也很重要。这些知识可以促进更具最佳，个性化的治疗方法，并推动新的药物治疗的发展。