Imaging the alpha7 nicotinic acetylcholine receptor in mild cognitive impairment

轻度认知障碍中 α7 烟碱乙酰胆碱受体的成像

• 批准号: 10563170
• 负责人: Arnold Bakker
• 金额: $ 76.37万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563170
• 关键词: Affinity; Age; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Autoantibodies; Binding; Biological; Biological Markers; Blood; Brain; Brain region; Cell Death; Cell surface; Cells; Cerebrospinal Fluid; Cerebrum; Cognition; Cognitive; Complement; Complex; Control Groups; Cytolysis; DNA; Data; Data Collection; Dementia; Diagnosis; Diagnostic; Disease; Elderly; Functional disorder; Goals; Image; Immune Plasma; Immunologic Markers; Impaired cognition; Individual; Individual Differences; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Microglia; Morbidity - disease rate; Neocortex; Neurons; Occipital lobe; Parietal Lobe; Participant; Pathology; Patients; Plasma; Population; Positron-Emission Tomography; Protein Microchips; Publishing; Research; Risk; Risk Factors; Senile Plaques; Staging; Synapses; Testing; Therapeutic; Work; abeta accumulation; alpha-bungarotoxin receptor; apolipoprotein E-4; basal forebrain; carrier status; cholinergic; cholinergic neuron; cognitive control; cognitive performance; cognitive testing; comparison control; comparison group; disability; experience; extracellular; follow-up; imaging biomarker; in vivo; in vivo imaging; inflammatory marker; mild cognitive impairment; neocortical; neuroimaging; non-smoking; normal aging; radiotracer; receptor binding; sex; tau Proteins; tau-1

PROJECT SUMMARY This project will assess the availability of the cerebral α7 nicotinic acetylcholine receptor (α7-nAChR) as a contributing factor in the early pathophysiology of Alzheimer's disease (AD). Converging data suggest that the α7-nAChR promotes accumulation of Aβ42 in cholinergic neurons, particularly in basal forebrain and neocortical regions where the α7-nAChR is more highly expressed. High cerebral α7-nAChR availability (as we have observed in normal aging), promotes intracellular sequestration of Aβ42 in cholinergic cells, and the Aβ42-α7-nAChR interaction functionally antagonizes the α7-nAChR, which may be linked to progressive, localized cell-death, synaptic loss, and aberrant neuronal activity long before spread of extracellular amyloid plaque. The Aβ42-α7-nAChR complex drives upregulated expression of the α7-nAChR, fueling its further interactions with soluble Aβ42 species. Based on published evidence and our preliminary data, we hypothesize that higher, cerebral α7-nAChR binding will be observed in patients with MCI, the prodrome to AD, compared to cognitively normal elderly controls using [18F]ASEM (ASEM) with positron emission tomography (PET). We further hypothesize that higher availability of α7-nAChR in targeted brain regions will be associated with 1. lower cognitive performance and 2. higher circulating, AD-relevant, biofluid biomarkers such as α7-nAChR autoantibodies within these participants. We will thus test for hypothesized high availability of the α7-nAChR in MCI compared to cognitively normal individuals, and its relationship to cognitive performance (Aim 1), as well as its correlation with targeted biofluid markers that include plasma α7- nAChR autoantibodies (Aim 2). Finally, in Aim 3, we will evaluate changes in α7-nAChR availability using ASEM PET and its relationship to cognitive performance and these biofluid markers between baseline and two-year follow-up in a subset of participants from Aims 1 and 2. The goal of this proposal is to test for high brain availability of the α7-nAChR in MCI and its relationship to cognition and circulating AD-relevant biomarkers - a critical step toward evaluating the α7-nAChR as an AD imaging biomarker with diagnostic and therapeutic implications.

项目摘要 该项目将评估脑α7烟碱乙酰胆碱受体（α7-NACHR）的可用性 促成阿尔茨海默氏病早期病理生理学（AD）的因素。 α7-NACHR促进Aβ42在胆碱能神经元中的积累，特别是在基础前脑和 α7-NACHR的新皮层区域高度表达。 我们已经在正常衰老中观察到），促进胆碱能细胞中Aβ42的细胞内螯合，并促进您 Aβ42-α7-NACHR相互作用在功能上与α7-NACHR拮抗，这可能与渐进性有关， 局部细胞死亡，突触损失和异常神经元活性早在细胞外淀粉样蛋白之前很久以前 斑块。 与可溶性Aβ42的相互作用。 假设在MCI患者中观察到的较高的脑α7-NACHR结合，前代至 AD，与使用[18F] ASEM（ASEM）发射的认知正常的老年人对照组相比 网格仪（PET）。 与1。认知表现和2。循环，广告相关的生物流体生物标志物相关 例如这些参与者中的α7-nachr自身抗体。 与认知正常个体相比，MCI中α7-NACHR的可用性及其与 认知性能（AIM 1），以及与包括等离子体α7-的靶向生物流体标记的相关性 NACHR自动抗体（AIM 2）。 ASEM PET及其与认知表现的关系以及基线和基线之间的这些生物流体标记 AIMS 1和2的一部分参与者的两年随访。这是测试高高高高的目标。 α7-NACHR在MCI中的大脑可用性及其与认知与广告相关的关系 生物标志物 - 评估α7 -NACHR作为AD成像生物标志物的批判性步骤 治疗意义。