Working Memory in Parkinson Disease: A Cognitive & Systems Neuroscience Approach

认知障碍和痴呆症是帕金森病(PD)最具破坏性的症状之一。 早期帕金森病患者表现出微妙的认知功能障碍，通常在出现运动症状时就已经存在。 发展，超过15%的帕金森病患者将达到轻度认知障碍(PD-MCI)的标准 最初的帕金森病诊断。在帕金森病患者的认知缺陷中，许多患者有特定的 工作记忆(WM)在几乎所有的高级认知功能中都扮演着重要的角色。在这里，我们 建议对帕金森病患者的WM功能障碍进行系统研究。这项研究的首要目标是 是为了确定大脑激活、网络连通性和因果神经动力学的变化 将这些变化与遗忘型MCI(AMCI)患者的WM缺陷进行对比，并 确定与多巴胺能相关的激活、连通性和因果动力学的变化 药物。在目标1中，我们将在功能磁共振成像(FMRI)期间使用WM任务来 确定PD-MCI和AMCI患者西医期间脑激活的差异模式。在目标2中，我们将 使用无任务功能磁共振成像概括我们在Aim 1中的发现，以确定 两组中与WM相关的脑区。最后，在目标3中，我们将调查 帕金森病与皮质多巴胺代谢和口服多巴胺相关的激活和内在连接 替补。我们将检验这样一种假设，即皮层-纹状体网络的弱相互作用是显著特征 这些相互作用的强度与帕金森病的个体差异有关。 我们提出的研究将导致对认知机制的新的和更好的理解 帕金森病和阿尔茨海默病的损害，这是老年人最常见的两种神经退行性疾病 人口。 我们研究的长期目标是更好地理解工作记忆和执行认知 帕金森氏病患者的缺陷及其神经生物学基础。我们建议的研究将提供 帕金森氏病患者工作记忆缺陷的系统和详细分析。刻画 这些赤字对于减少与以下方面相关的大量人力和财政成本至关重要 帕金森病患者的认知功能障碍，并最终促进对患者的更好治疗。

Cognitive impairment and dementia are among the most devastating symptoms of Parkinsons disease (PD). Early PD patients exhibit subtle cognitive dysfunction that is often already present by the time motor symptoms develop, and over 15% of PD patients will fulfill criteria for Mild Cognitive Impairment (PD-MCI) at the time of the initial PD diagnosis. Among the cognitive deficits seen in PD, many patients have specific impairment of Working Memory (WM), which plays an important role in virtually all higher-order cognitive functions. Here, we propose to initiate a systematic study of WM dysfunction in PD patients. The overarching goals of this study are to determine changes in brain activation, network connectivity, and causal neural dynamics associated with WM deficits in patients with PD, contrast these changes with WM deficits in amnestic-MCI (aMCI) patients, and determine the changes in activation, connectivity, and causal dynamics associated with dopaminergic medications. In Aim 1 we will use a WM task during functional Magnetic Resonance Imaging (fMRI) to determine the differential patterns of brain activation during WM in PD-MCI and aMCI. In Aim 2, we will generalize our findings from Aim 1 using task-free fMRI to determine the intrinsic connectivity differences in brain regions associated with WM in the two groups. Finally, in Aim 3 we will investigate changes in patterns of activation and intrinsic connectivity in PD associated with cortical dopamine metabolism and oral dopamine replacement. We will test the hypothesis that weak cortico-striatal network interactions are prominent features of WM deficits in PD, and that the strength of these interactions is related to individual differences in deficits. Our proposed studies will lead to new and improved understanding of the mechanisms underlying cognitive impairment in PD and Alzheimers disease, the two most common neurodegenerative disorders in the aging population. The long-term goal of our research is to better understand the working memory and executive cognitive deficits, and their neurobiological bases, in people with Parkinsons disease. Our proposed studies will provide a systematic and detailed analysis of working memory deficits in Parkinsons disease patients. Characterizing these deficits is profoundly important to reducing the substantial human and financial costs associated with cognitive dysfunction in PD, and ultimately promoting better treatments for patients.