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

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上，而忽视了 情绪变化可能是阿尔茨海默病最早的表现之一。分子正电子发射 断层扫描(PET)检测到β淀粉样蛋白和tau蛋白摄取增加，这两种蛋白是神经病理的 AD的特征，在存活的AD患者和有轻度认知障碍(MCI)的患者中，临床期 这比公元前要早。认知正常成人的淀粉样阳性(淀粉样阳性)PET扫描提示临床前 AD，这一阶段可能在认知症状出现之前数年或数十年开始。除了认知之外 情绪缺陷和改变在MCI和AD中也很常见，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一种病态的 衰老过程和早期神经退行性改变的存在。情绪的实验室研究 生理和行为有可能揭示阿尔茨海默病情感变化的生物学基础，并 确定AD情绪轨迹如何以及何时偏离正常年龄的情绪轨迹。的个体差异 包括性别和遗传在内的生物变量(AD风险因素、载脂蛋白Ɛ4以及单核苷酸 多态和基因表达谱)可以改变疾病进展或与 随着时间的推移，情绪会发挥作用。拟议项目的总体目标是阐明神经系统和 阿尔茨海默病情绪变化背后的遗传因素。特定于解剖学的情绪标记物可用于 拓宽当前对早期AD表型的概念化，确定情感性最高风险的亚型 症状，监测症状进展，或跟踪疾病相关的下降，在无症状或 症状轻微的个体。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例淀粉样蛋白+健康对照组，50例淀粉样蛋白+MCI患者，50例淀粉样蛋白+MCI患者 广告。参与者将接受基线遗传分析以及对情绪的实验室评估(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。这一建议的中心假设是情绪失调是 AD的早期特征，可通过客观的生理和行为测量进行评估，直接 情绪系统的读数。我们将解决三个主要目标。在目标1中，我们将确定公元多早 情绪轨迹与正常衰老的情绪轨迹不同。在目标2中，我们将确定情绪回路是如何衰退的 与随着时间的推移减少情绪调节有关。在目标3中，我们将研究性别和基因变异是如何 与整个广告连续体中情绪的个体差异有关。这个项目有推进的潜力。 阿尔茨海默病早期情绪改变的神经生物学基础模型。

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.