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: 10094179
• 负责人: Arnold Bakker
• 金额: $ 78.17万
• 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/10094179
• 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; 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; Neurons; Occipital lobe; Parietal Lobe; Participant; Pathology; Patients; Plasma; Population; Positron-Emission Tomography; Protein Microchips; Publishing; Research; Risk; Risk Factors; Senile Plaques; Staging; Structure; Synapses; Testing; Therapeutic; Work; abeta accumulation; alpha-bungarotoxin receptor; basal forebrain; base; carrier status; cholinergic; cholinergic neuron; cognitive performance; cognitive testing; 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; 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.

项目总结 该项目将评估大脑α7烟碱型乙酰胆碱受体(α7-nAChR)作为一种 阿尔茨海默病(AD)早期病理生理学的贡献因素。汇聚的数据表明， α7-nAChR促进胆碱能神经元Aβ42的积聚，特别是在基底前脑和 α7-nAChR高表达的新皮质区域。高大脑α7-nAChR可用性(AS 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，并且 β42-α7-nAChR相互作用在功能上拮抗α7-nAChR，这可能与渐进的， 早在细胞外淀粉样蛋白扩散之前很久的局限性细胞死亡、突触丢失和神经元活动异常 斑块。Aβ42-α7-nAChR复合体驱动α7-nAChR的上调表达，进一步促进其 与可溶性Aβ42种的相互作用。根据已公布的证据和我们的初步数据，我们 假设在轻度认知障碍患者中观察到更高的大脑α7-nAChR结合，前驱症状为 AD，与使用正电子发射的[18F]ASEM(ASEM)的认知正常老年人对照 断层扫描(PET)。我们进一步假设，α7-nAChR在目标脑区域的更高可用性将 与1.较低的认知能力和2.较高的循环、AD相关的生物体液生物标志物有关 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 α7-nAChR在轻度认知障碍患者中的可用性及其与认知正常个体的关系 认知表现(目标1)，以及它与包括血浆α7- NAChR自身抗体(AIM 2)。最后，在目标3中，我们将使用以下工具评估α7-nAChR可用性的变化 ASEM正电子发射计算机体层摄影及其与认知能力和这些生物流体标志物的关系 对来自目标1和目标2的参与者的子集进行了两年的随访。该提案的目标是测试HIGH 轻度认知障碍患者α7-nAChR的脑可利用度及其与认知和循环AD相关的关系 生物标记物-评估α7的关键一步-nAChR作为AD成像生物标记物具有诊断和 治疗方面的影响。