Neurobiological Basis of Emotion Regulation Trajectories in Early Alzheimer's Disease

早期阿尔茨海默病情绪调节轨迹的神经生物学基础

• 批准号: 10177830
• 负责人: Virginia Emily Sturm
• 金额: $ 75.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177830
• 关键词: Address; Adult; Affect; Affective; Affective Symptoms; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anatomic Models; Anatomy; Anxiety; Arousal; Atrophic; Autonomic nervous system; Behavior; Biological; Biological Markers; Brain; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Data; Detection; Deterioration; Disease; Disease Progression; Early Diagnosis; Emotional; Emotional Stability; Emotions; Empathy; Episodic memory; Facial Expression; Family; Gene Expression; Generations; Genetic; Genetic Variation; Goals; Imaging Techniques; Impaired cognition; Individual; Individual Differences; Interpersonal Relations; Investigation; Laboratories; Laboratory Study; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Memory Loss; Modeling; Molecular; Monitor; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neurologic; Neuropsychological Tests; Participant; Patients; Pattern; Phase; Physiology; Positron-Emission Tomography; Process; Research; Rest; Risk; Risk Factors; Sex Differences; Signs and Symptoms; Single Nucleotide Polymorphism; Social Behavior; Societies; Structure; Support System; Symptoms; System; Temporal Lobe; Time; Visit; Woman; apolipoprotein E-4; base; contagion; disease phenotype; disorder subtype; emotion dysregulation; emotion regulation; emotional behavior; emotional experience; experience; genetic analysis; improved; men; mild cognitive impairment; network dysfunction; normal aging; novel marker; pathological aging; pre-clinical; preservation; relating to nervous system; sex; support network; tau Proteins; uptake

ABSTRACT The majority of research on early Alzheimer's disease (AD) has focused on cognition and has overlooked the possibility that changes in emotion may be one of AD's first manifestations. Molecular positron emission tomography (PET) scans detect elevated uptake of beta amyloid and tau, proteins that are neuropathological hallmarks of AD, in living patients with AD and in those with mild cognitive impairment (MCI), the clinical phase that precedes AD. An amyloid positive (amyloid+) PET scan in cognitively normal adults indicates preclinical AD, a phase that may begin years or decades before cognitive symptoms emerge. In addition to cognitive deficits, alterations in emotion are also common in MCI and AD and reflect changes in the neural systems that support emotion generation and emotion regulation. Declining emotion regulation may signify a pathological aging process and the presence of incipient neurodegenerative changes. Laboratory studies of emotion physiology and behavior have the potential to uncover the biological basis of affective change in AD and to determine how and when AD emotion trajectories diverge from those of normal aging. Individual differences in biological variables including sex and genetics (AD risk factor Apolipoprotein Ɛ4 as well as single nucleotide polymorphisms and gene expression profiles) may modify disease progression or relate to variability in emotion functioning over time. The overall goal of the proposed project is to elucidate the neural systems and genetic factors that underlie emotion change in AD. Anatomically-specific markers of emotion could be used to broaden current conceptualizations of early AD phenotypes, identify subtypes at greatest risk for affective symptoms, monitor symptom progression, or track disease-related decline in clinical trials of asymptomatic or mildly symptomatic individuals. We will conduct a longitudinal study of 200 participants: 50 amyloid negative healthy controls, 50 amyloid+ healthy controls, 50 amyloid+ patients with MCI, and 50 amyloid+ patients with AD. Participants will undergo baseline genetic analyses as well as laboratory assessments of emotion (i.e., autonomic nervous system reactivity, facial expression, and subjective experience) and magnetic resonance imaging at three annual research visits. The central hypothesis of this proposal is that emotion dysregulation is an early feature of AD that can be assessed via objective measures of physiology and behavior, direct readouts of emotion systems. We will address three key aims. In Aim 1, we will determine how early AD emotion trajectories diverge from those of normal aging. In Aim 2, we will identify how emotion circuit decline relates to decreasing emotion regulation over time. In Aim 3, we will examine how sex and genetic variation relate to individual differences in emotion across the AD continuum. This project has the potential to advance current models of the neurobiological basis of emotion change in early AD.

摘要 大多数关于早期阿尔茨海默病（AD）的研究都集中在认知方面，而忽视了 情绪变化可能是AD的最初表现之一。分子正电子发射 断层扫描（PET）检测到β淀粉样蛋白和tau蛋白的摄取增加，这些蛋白是神经病理性的 AD的标志，在患有AD的存活患者和患有轻度认知障碍（MCI）的患者中， 在AD之前。认知正常成人的淀粉样蛋白阳性（淀粉样蛋白+）PET扫描表明临床前 AD是一个可能在认知症状出现前开始几年或几十年就开始的阶段。除了认知 在MCI和AD中，情感的缺陷、改变也很常见，并反映了神经系统的变化， 支持情绪生成和情绪调节。情绪调节能力下降可能意味着 衰老过程和早期神经退行性变化的存在。情绪的实验室研究 生理学和行为学有可能揭示AD情感变化的生物学基础， 确定AD情绪轨迹如何以及何时与正常衰老的情绪轨迹不同。的个体差异 生物学变量包括性别和遗传学（AD危险因素载脂蛋白A4以及单核苷酸 多态性和基因表达谱）可以改变疾病进展或与 情绪功能随着时间的推移。拟议项目的总体目标是阐明神经系统， 遗传因素是导致AD患者情绪变化的基础。解剖学上特定的情感标记可以用来 拓宽了目前早期AD表型的概念，确定了情感障碍风险最大的亚型， 症状，监测症状进展，或跟踪疾病相关的下降，在临床试验中的无症状或 轻度症状的个体。我们将对200名参与者进行纵向研究：50名淀粉样蛋白阴性 健康对照组、50名淀粉样蛋白+健康对照组、50名淀粉样蛋白+MCI患者和50名淀粉样蛋白+MCI患者。 AD.参与者将接受基线遗传分析以及情绪的实验室评估（即， 自主神经系统反应性、面部表情和主观体验）和磁共振 在三次年度研究访问中进行成像。这一建议的核心假设是，情绪失调是 AD的早期特征，可以通过生理学和行为的客观测量进行评估，直接 情绪系统的读数。我们将实现三个关键目标。在目标1中，我们将确定AD 情绪轨迹与正常衰老的轨迹不同。在目标2中，我们将确定情绪回路是如何衰退的。 随着时间的推移，情绪调节能力下降。在目标3中，我们将研究性别和遗传变异 与AD连续体中情绪的个体差异有关。这个项目有潜力推进 AD早期情绪变化的神经生物学基础的当前模型。