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 该项目将评估大脑α7烟碱乙酰胆碱受体（α7-nAChR）作为一种 在阿尔茨海默病（AD）的早期病理生理学的贡献因素。汇总数据表明， α7-nAChR促进Aβ42在胆碱能神经元中的蓄积，尤其是在基底前脑， α7-nAChR更高表达的新皮层区域。高脑α7-nAChR可用性（如 我们在正常衰老中观察到），促进胆碱能细胞中Aβ42的细胞内隔离， Aβ42-α7-nAChR相互作用在功能上拮抗α7-nAChR，这可能与进行性， 在细胞外淀粉样蛋白扩散之前很久，局部细胞死亡、突触丧失和异常神经元活动 斑块Aβ42-α7-nAChR复合物驱动α7-nAChR的上调表达，进一步促进了其在细胞内的表达。 与可溶性Aβ42相互作用。根据已发表的证据和我们的初步数据，我们 假设在MCI患者中观察到更高的脑α7-nAChR结合，MCI是MCI的前驱症状， AD，与认知正常老年对照相比，使用[18 F]ASEM（ASEM）和正电子发射 断层扫描（PET）。我们进一步假设，目标大脑区域中α7-nAChR的可用性更高， 与1相关联。较低的认知表现和2.更高的循环、AD相关生物液体生物标志物 例如这些参与者体内的α7-nAChR自身抗体。因此，我们将测试假设的高 与认知正常个体相比，MCI中α7-nAChR的可用性，及其与 认知能力（目标1），以及其与靶向生物液体标志物（包括血浆α7- nAChR自身抗体（Aim 2）。最后，在目标3中，我们将评估α7-nAChR可用性的变化， ASEM PET及其与认知能力和基线和基线之间的这些生物流体标志物的关系 在目标1和2的参与者子集中进行两年随访。该提案的目标是测试高 MCI患者α7-nAChR的脑利用度及其与认知和循环AD相关性的关系 生物标志物-评估α7-nAChR作为AD成像生物标志物的关键一步， 治疗意义