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.

项目概要 虽然阿尔茨海默病 (AD) 相关的 β-淀粉样蛋白 (Aβ) 和 tau 蛋白病理学的发展是相关的 随着人群大脑结构和认知功能的下降，存在相当大的异质性 大脑多巴胺系统的个体差异代表了这些影响。 先前的研究表明，Aβ 和 tau 蛋白病理学对大脑结构和功能的影响具有令人信服的调节作用。 确定“最佳”遗传多态性可增加多巴胺 D2 受体亲和力 （DRD2 C957T；rs6277）与更大的皮质厚度相关，而驱动这种效应的机制。 目前尚不清楚，多巴胺具有神经营养作用，D2 受体介导许多神经保护作用 可以对抗 AD 过程的功能，包括减少与神经炎症相关的功能。 尽管存在病理情况，但仍能成功维持认知功能，与较高的 D2 受体可用性相关 我们认为 DRD2 T/T 基因型支持 AD 恢复能力。 相关的 tau 蛋白和 Aβ 病理学分析将重点关注认知正常和轻度认知障碍群体。 为此，我们将利用建立成功的 AD 恢复机制。 阿尔茨海默病神经影像倡议 (ADNI) 数据集旨在实现以下具体目标： 尽管存在 Aβ，但确定 DRD2 T/T 基因型在赋予更大皮质厚度中的作用 ([18F]Florbetapir/Florbetaben) 和 tau ([18F]Flortaucipir PET) 病理横断面（目标 1）。 通过探究 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进行横断面和纵向测量 我们将检验 T/T 基因型与好于预期相关的假设。 最后，我们将使用临床跟踪纵向临床衰退。 痴呆量表 – 方框总和以及皮质厚度的纵向下降，以确定痴呆程度 T/T 基因型预测较慢的临床衰退和大脑维持（目标 3）。 这些目标将提供新的证据，证明多巴胺系统与 AD 病理相互作用，从而影响衰老 轨迹，并将支持针对倾向于降低多巴胺系统的个体的治疗目标 D2 亲和力。