Emotion alterations across the Alzheimer's disease spectrum

摘要 情绪和社会行为的改变是阿尔茨海默病(AD)的早期特征，但被忽视了。在公元后， β淀粉样蛋白(Aβ)和tau蛋白逐渐积累，这是一个导致 分布式大脑网络中的神经退化和功能连接改变。情节记忆 衰退是典型的健忘型AD的一个显著特征，但AD也可以导致非典型 执行/遗忘障碍，语言(即对数变异的原发性进行性失语[lvPPA])，以及 视觉空间(即，皮质后萎缩[PCA])综合征。在典型AD中，默认模式为网络功能障碍 伴随着显著网络中功能连接的提升，这是一个支持情绪的系统 生成和内感。AD中增强的显著网络连接与更高的 焦虑等情感症状。我们之前的研究发现，特定类型的情感移情， 情感分享的一种基本形式，在典型的AD中升高，与默认模式的网络萎缩有关。 非典型AD综合征中是否存在情绪升高尚不清楚，但临床提示 和神经成像数据。有新的证据表明，情感共鸣的进步即使在 临床前阿尔茨海默病，这是一个先兆阶段，在这个阶段，人们在生物标志物检测中有AD病理迹象，但缺乏 认知症状。这一建议的一个中心假设是早期神经病理和神经退行性变 在易受AD影响的网络中，解除了突出网络的抑制，并提升了整个AD的情绪功能 综合症。更详细地了解阿尔茨海默病的情绪将有助于通过拓宽诊断 目前对每个综合征的概念化，以确定表明早期存在的情绪测量 AD，并发现随着神经病理影响与情绪相关的大脑网络而变化的新生物标记物。在……里面 在拟议的研究中，我们将对情绪(即自主神经)进行基于实验室的评估 Aβ升高提示AD患者的系统活动、面部行为和主观体验 (aβ+)和tau沉积在分子正电子发射计算机断层扫描上(110lvPPA，45lvPPA和45pca)， 以及有和没有AD病理的150名老年健康对照组(75Aβ+和75Aβ-)，其tau水平各不相同 病理学。通过将情绪测量与临床数据、结构和功能连接、Aβ和tau联系起来 负担和情感症状，我们将解决三个关键目标。在目标1中，我们将量化情感、同理心、 AD综合征和Aβ+健康对照的社会行为。在目标2中，我们将勾勒出结构和 功能神经网络是整个AD频谱中情绪变化的基础。在目标3中，我们将阐明 Aβ和tau病理、情绪系统功能和情感症状之间的关系。通过锻造 情绪测量、神经网络功能障碍、情感症状、Aβ和tau沉积之间的联系， 这项拟议的研究将有助于拓宽AD最早表现的模型，并阐明 特定的神经病理改变会改变情绪系统，并与情感症状有关。

ABSTRACT Changes in emotion and social behavior are early yet overlooked features of Alzheimer's disease (AD). In AD, there is progressive accumulation of beta amyloid (Aβ) and tau proteins, a pathological process that leads to neurodegeneration and functional connectivity alterations in distributed brain networks. Episodic memory decline is a hallmark feature of typical amnestic AD presentations, but AD can also cause atypical dysexecutive/amnestic, language (i.e., logopenic variant primary progressive aphasia [lvPPA]), and visuospatial (i.e., posterior cortical atrophy [PCA]) syndromes. In typical AD, default mode network dysfunction is accompanied by elevated functional connectivity in the salience network, a system that supports emotion generation and interoception. Enhanced salience network connectivity in AD is associated with greater affective symptoms such as anxiety. Our previous studies have found that specific types of emotional empathy, a rudimentary form of affect-sharing, are elevated in typical AD and relate to default mode network atrophy. Whether emotion elevations are present in atypical AD syndromes is unknown but are suggested by clinical and neuroimaging data. There is emerging evidence that gains in emotional empathy are evident even in preclinical AD, a prodromal phase in which people have signs of AD pathology on biomarker testing but lack cognitive symptoms. A central hypothesis of this proposal is that early neuropathology and neurodegeneration in AD-vulnerable networks disinhibits the salience network and elevates emotion functioning across AD syndromes. A more detailed understanding of emotion in AD will help to improve diagnosis by broadening current conceptualizations of each syndrome, to identify emotion measures that suggest the presence of early AD, and to uncover new biomarkers that change as neuropathology affects emotion-relevant brain networks. In the proposed studies, we will conduct laboratory-based assessments of emotion (i.e., autonomic nervous system activity, facial behavior, and subjective experience) in 200 people with AD, as indicated by elevated Aβ (Aβ+) and tau deposition on molecular PET scans (110 amnestic/dysexecutive AD, 45 lvPPA, and 45 PCA), and 150 older healthy controls with and without AD pathology (75 Aβ+ and 75 Aβ-) with varying levels of tau pathology. By relating emotion measures to clinical data, structural and functional connectivity, Aβ and tau burden, and affective symptoms, we will address three key aims. In Aim 1, we will quantify emotion, empathy, and social behavior in AD syndromes and Aβ+ healthy controls. In Aim 2, we will delineate the structural and functional neural networks underlying emotion alterations across the AD spectrum. In Aim 3, we will elucidate associations among Aβ and tau pathology, emotion system functioning, and affective symptoms. By forging links among measures of emotion, neural network dysfunction, affective symptoms, and Aβ and tau deposition, the proposed research will help to broaden models of AD's earliest manifestations and to elucidate how specific neuropathological changes alter emotion systems and relate to affective symptoms.