The role of cortical nicotinic receptors in pathological brain oscillations in Parkinson's disease cognitive impairment

皮质烟碱受体在帕金森病认知障碍病理性脑振荡中的作用

• 批准号: 10666717
• 负责人: Kelly Alexander Mills
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666717
• 关键词: Affect; Affinity; Age; Animals; Anterior; Area; Attention; Basal Ganglia; Binding; Biological Markers; Brain; Brain region; Characteristics; Chemistry; Cholinergic Receptors; Cognition; Cognitive deficits; Coupling; Data; Deep Brain Stimulation; Dementia; Denervation; Development; Disease; Dopamine; Electrodes; Electrophysiology (science); Etiology; Frequencies; Functional disorder; Future; Generations; Healthcare; Hippocampus; Image; Impaired cognition; Intervention; Left; Ligands; Link; Maps; Measures; Mediating; Memory; Mentored Patient-Oriented Research Career Development Award; Movement; Neurobiology; Neurotransmitters; Nicotinic Receptors; Noise; Operative Surgical Procedures; Parietal; Parietal Lobe; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Pattern; Perception; Persons; Pharmacotherapy; Phase; Positron-Emission Tomography; Prefrontal Cortex; Principal Investigator; Problem Solving; Quality of life; Research Personnel; Research Project Grants; Rest; Role; Severities; Short-Term Memory; Signal Transduction; Structure; Structure of subthalamic nucleus; Symptoms; System; Tremor; United States; Visuospatial; brain abnormalities; cholinergic; cingulate cortex; cognitive control; cognitive function; cognitive impairment in Parkinson' s; cognitive testing; disability; executive function; improved; inattention; insight; intervention effect; molecular imaging; motor symptom; network dysfunction; neurophysiology; neuroregulation; pharmacologic; radioligand; radiotracer; receptor; temporal measurement; trend; Affect; Affinity; Age; Animals; Anterior; Area; Attention; Basal Ganglia; Binding; Biological Markers; Brain; Brain region; Characteristics; Chemistry; Cholinergic Receptors; Cognition; Cognitive deficits; Coupling; Data; Deep Brain Stimulation; Dementia; Denervation; Development; Disease; Dopamine; Electrodes; Electrophysiology (science); Etiology; Frequencies; Functional disorder; Future; Generations; Healthcare; Hippocampus; Image; Impaired cognition; Intervention; Left; Ligands; Link; Maps; Measures; Mediating; Memory; Mentored Patient-Oriented Research Career Development Award; Movement; Neurobiology; Neurotransmitters; Nicotinic Receptors; Noise; Operative Surgical Procedures; Parietal; Parietal Lobe; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Pattern; Perception; Persons; Pharmacotherapy; Phase; Positron-Emission Tomography; Prefrontal Cortex; Principal Investigator; Problem Solving; Quality of life; Research Personnel; Research Project Grants; Rest; Role; Severities; Short-Term Memory; Signal Transduction; Structure; Structure of subthalamic nucleus; Symptoms; System; Tremor; United States; Visuospatial; brain abnormalities; cholinergic; cingulate cortex; cognitive control; cognitive function; cognitive impairment in Parkinson' s; cognitive testing; disability; executive function; improved; inattention; insight; intervention effect; molecular imaging; motor symptom; network dysfunction; neurophysiology; neuroregulation; pharmacologic; radioligand; radiotracer; receptor; temporal measurement; trend

7. PROJECT SUMMARY/ABSTRACT Cognitive impairment in Parkinson's disease (PD) drives substantial disability and US healthcare spending, yet further understanding of the multiple possible mechanisms is needed in order to develop treatments. Cognitive deficits in PD are associated with cholinergic denervation mediated through regional α4β2 nicotinic cholinergic receptor (α4β2-nAChR) binding changes. Animal evidence implicates the same receptors in the generation of brain oscillations that are a mechanism of normal brain function. Abnormal oscillations in the β band or phase- amplitude coupling (PAC) between β and γ frequencies correlate with motor symptoms in PD. Abnormal oscillations also exist in brain regions and networks associated with cognitive functions. Our overall objective of this exploratory R21 is to understand the relationship between α4β2-nAChR signaling and pathological brain oscillations in regions involved in cognitive impairment in PD. With converging evidence for the role of α4β2- nAChR's in PD-related cognitive dysfunction and slow oscillations, we hypothesize that defective signaling through α4β2-nAChR's is related to pathological oscillations and oscillation coupling and is one mechanism of cognitive impairment in PD. The proposed study combines cognitive testing, molecular imaging of α4β2- nAChR's with a unique radioligand ([18F]XTRA) with good signal-to-noise characteristics for imaging cortical and hippocampal regions, and intracranial recordings from STN and subdural electrodes over cortical regions known to a) be involved in the cognitive deficits seen in PD, b) have elevated β oscillation power in PD, and c) show abnormal α4β2-nAChR availability in PD. Aim 1 is to determine whether α4β2-nAChR availability in persons with PD positively correlates with the cortical β power or β-γ phase-amplitude coupling and STN- cortex coherence as measured by intracranial recordings over regions involved in cognition during deep brain stimulation (DBS) surgery. We hypothesize: 1) Higher α4β2-nAChR availability (BPND) in the left DLPFC and right parietal cortex will be associated with higher β power and β-γ PAC recorded via a subdural electrode strip in these regions at rest, adjusting for age; and 2) Higher α4β2-nAChR availability will be associated with greater subthalamic nucleus (STN) β power locally and β phase coherence with the left DLPFC and right parietal cortex, regions associated with cognitive dysfunction in PD. Aim 2 is to evaluate whether α4β2-nAChR availability and β band power or β-γ phase-amplitude coupling over the DLPFC and parietal cortices are associated with executive and visuospatial dysfunction in PD, where we hypothesize: 1) Higher α4β2-nAChR availability and LFP β band power and/or β-γ PAC in the left DLPFC will correlate with worse problem-solving, working memory, and set-shifting, and in the right parietal cortex, with worse visuospatial perception, and 2) Higher associative STN LFP β band power and α4β2-nAChR availability will correlate with deficits in attention. This study would generate a neurophysiologic biomarker and inform development of both pharmacologic and neuromodulation treatments for cognitive impairment in PD.

7。项目摘要/摘要 帕金森氏病（PD）的认知障碍驱动了大量残疾和美国医疗保健支出，但 为了开发治疗，需要进一步了解多种可能的机制。认知的 PD中的缺陷与通过区域α4β2烟碱胆碱能介导的胆碱能神经治疗有关 受体（α4β2-NACHR）结合变化。动物证据在一代中实现了相同的受体 脑振荡是正常脑功能的机制。 β带或相位异常振荡 β和γ频率之间的振幅耦合（PAC）与PD中的运动症状相关。异常 与认知功能相关的大脑区域和网络也存在振荡。我们的总体目标 该探索性R21是了解α4β2-NACHR信号传导与病理大脑之间的关系 涉及PD认知障碍区域的振荡。与α4β2-的作用的融合证据 NACHR在与PD相关的认知功能障碍和缓慢的振荡中，我们假设有缺陷的信号传导 通过α4β2-NACHR与病理振荡和振荡耦合有关，是一种机制 PD的认知障碍。提出的研究结合了认知测试，α4β2-的分子成像 NACHR具有独特的放射线（[18F] Xtra），具有良好的信号到噪声特征用于成像皮质 皮质区域的STN和硬膜下电极的海马区域以及颅内记录 a）参与PD中所见的认知定义，b）在PD中具有升高的β振荡能力，C） 在PD中显示异常的α4β2-NACHR可用性。 AIM 1是确定是否在 具有PD的人与皮质β功率或β-γ相位振幅耦合和stn-正相关 皮质相干性通过颅内记录在深脑期间参与认知的区域测量 刺激（DBS）手术。我们假设：1）左DLPFC和 右顶叶皮层将与较高的β功率和通过硬膜下电极条记录的β-γpac相关 在这些地区休息，适应年龄； 2）较高的α4β2-NACHR的可用性将与 丘脑下核（STN）β功率较大，与左DLPFC和右β相一致 顶皮层，与PD中的认知功能障碍相关的区域。 AIM 2是评估α4β2-NACHR是否 可用性和β带功率或DLPFC和顶叶上的β-γ相位振幅耦合是 与PD中的执行和视觉功能障碍相关，我们假设：1）较高的α4β2-NACHR 左DLPFC中的可用性和LFPβ带功率和/或β-γPAC将与解决问题的较差相关， 工作记忆和设置转移，在正确的顶叶皮层中，视觉感知较差，2） 较高的关联STN LFPβ带功率和α4β2-NACHR的可用性将与注意力不足有关。 这项研究将产生神经生理生物标志物，并为药理学和 PD中认知障碍的神经调节治疗。