Dopaminergic mechanisms of resilience to Alzheimer's disease neuropathology

阿尔茨海默病神经病理学恢复的多巴胺能机制

• 批准号: 10809199
• 负责人: Anne Shively Berry
• 金额: $ 43.68万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809199
• 关键词: Address; Adult; Affect; Affinity; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Anti-Inflammatory Agents; Automobile Driving; Behavior; Brain; Clinical; Clinical dementia rating scale; Cognition; Cognitive; DRD2 gene; Data; Data Set; Dementia; Development; Dopamine; Dopamine D2 Receptor; Elderly; Genes; Genetic Polymorphism; Genotype; Heterogeneity; Human; Impaired cognition; Individual; Individual Differences; Intervention; Link; Maintenance; Measures; Mediating; Memory; Neuromodulator; Pathology; Play; Population; Positron-Emission Tomography; Process; Proxy; Publishing; Research; Role; Standardization; Structure; Sum; System; Testing; Thick; Thinness; Variant; beta amyloid pathology; brain health; cognitive function; cognitive performance; cognitive reserve; dopamine system; entorhinal cortex; executive function; formycin triphosphate; genetic variant; interest; mild cognitive impairment; nerve supply; neural; neuroimaging; neuroinflammation; neuromechanism; neuropathology; neuroprotection; novel; pre-clinical; preservation; receptor binding; receptor function; resilience; resilience factor; secondary analysis; tau Proteins; therapeutic target; uptake; β-amyloid burden

PROJECT SUMMARY While the development of Alzheimer’s disease (AD)-related β-amyloid (Aβ) and tau pathology is associated with declines in brain structure and cognitive function on a population level, there is considerable heterogeneity in these effects across individuals. Individual differences in the brain’s dopamine system represent a compelling moderator of Aβ and tau pathology’s effects on brain structure and function. Previous research has established that an “optimal” genetic polymorphism presumed to increase dopamine D2 receptor affinity (DRD2 C957T; rs6277) is associated with greater cortical thickness. While the mechanisms driving this effect are not known, dopamine can be neurotrophic and D2 receptors mediate a number of neuroprotective functions that may counteract AD processes including reduction of neuroinflammation. Relevant to the successful maintenance of cognitive function despite pathology, higher D2 receptor availability is associated with better executive function and memory. We propose the DRD2 T/T genotype supports resilience to AD- related tau and Aβ pathology. Analyses will focus on cognitively normal and mild cognitive impairment groups for which establishing the mechanisms of successful AD resilience are most relevant. We will use the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to pursue the following Specific Aims. We will first establish a role of the DRD2 T/T genotype in conferring greater cortical thickness despite Aβ ([18F]Florbetapir/Florbetaben) and tau ([18F]Flortaucipir PET) pathology cross-sectionally (Aim 1). Next, we will investigate the role of DRD2 T/T genotype in cognitive reserve by probing genotype x pathology interactions in cross-sectional and longitudinal measures of executive function and memory using the Preclinical Alzheimer Cognition Composite. We will test the hypothesis that the T/T genotype is associated with better-than-expected cognition given tau and Aβ burden (Aim 2). Finally, we will track longitudinal clinical decline using the Clinical Dementia Scale – Sum of Boxes and longitudinal decline in cortical thickness to determine the extent to which the T/T genotype predicts slower clinical decline and brain maintenance (Aim 3). The successful completion of these aims will provide novel evidence that the dopamine system interacts with AD pathology to affect aging trajectories, and will support therapeutic targeting of the dopamine system for individuals predisposed to lower D2 affinity.

项目摘要 而阿尔茨海默氏病（AD）相关的β-淀粉样蛋白（Aβ）和TAU病理的发展是相关的 随着人群水平上的大脑结构和认知功能的下降，存在相当大的异质性 在各个个体的影响中。大脑多巴胺系统的个体差异代表 Aβ和TAU病理学对大脑结构和功能的影响的引人注目的主持人。先前的研究已有 确定假定增加多巴胺D2受体亲和力的“最佳”遗传多态性 （DRD2 C957T; rs6277）与更大的皮质厚度有关。而驱动这种效果的机制 尚不清楚，多巴胺可以是神经营养性的，而D2受体介导许多神经保护作用 可以抵消AD过程的功能，包括减少神经炎症。与 成功维持认知功能任务病理学，较高的D2受体可用性与 具有更好的执行功能和记忆。我们提出的DRD2 T/T基因型有助于对AD-的弹性 相关的TAU和Aβ病理。分析将集中于认知正常和轻度认知障碍组 为此，建立成功的AD弹性机制是最相关的。我们将使用 阿尔茨海默氏病神经影像学倡议（ADNI）数据集，以追求以下特定目标。我们将首先 建立DRD2 T/T基因型在授权更大的皮质厚度目的地Aβ中的作用 （[18f] florbetapir/florbetaben）和tau（[18f] flortaucipir宠物）横截面（AIM 1）。接下来，我们会的 通过探测基因型X病理相互作用，研究DRD2 T/T基因型在认知储备中的作用 使用临床前阿尔茨海默氏症对执行功能和记忆的横截面和纵向测量 认知综合。我们将测试T/T基因型与预期更好的假设 认知给予tau和aβ伯嫩（AIM 2）。最后，我们将使用临床跟踪纵向临床下降 痴呆量量表 - 盒子的总和和皮质厚度的纵向下降，以确定 T/T基因型预测降低了临床下降和脑部维护（AIM 3）。成功完成 这些目标将提供新的证据，表明多巴胺系统与AD病理相互作用以影响衰老 轨迹，并将支持多巴胺系统的治疗靶向易于降低的个体 D2亲和力。