Emotion alterations across the Alzheimer's disease spectrum

摘要 情绪和社会行为的变化是阿尔茨海默病（AD）的早期但被忽视的特征。在AD中， β-淀粉样蛋白（Aβ）和tau蛋白进行性积累，这是一种病理过程， 神经退行性变和功能连接性改变。情景记忆 衰退是典型的遗忘型AD表现的标志性特征，但AD也可引起非典型的 执行障碍/遗忘，语言（即，逻辑缺失变异型原发性进行性失语[lvPPA]），以及 视觉空间（即，后皮质萎缩[PCA]）综合征。在典型的AD中，默认模式网络功能障碍 伴随着显著性网络（一个支持情感的系统）中功能连接的提升 生成和内感受。AD中增强的显著性网络连接与更大的 情感症状，如焦虑。我们之前的研究已经发现，特定类型的情感同理心， 一种情感分享的基本形式，在典型的AD中升高，并与默认模式网络萎缩有关。 情绪升高是否存在于非典型AD综合征尚不清楚，但临床研究表明， 和神经成像数据。有新的证据表明，即使在老年人中， 临床前AD是一个前驱期，在此阶段，人们在生物标志物检测中有AD病理学迹象，但缺乏 认知症状这一建议的一个中心假设是，早期神经病理学和神经退行性变 在易受AD影响的网络中， 综合征更详细地了解AD中的情绪将有助于通过扩大 目前的概念化的每一个综合征，以确定情绪措施，表明存在的早期 AD，并发现新的生物标志物，随着神经病理学影响情绪相关的大脑网络而变化。在 在拟议的研究中，我们将进行基于实验室的情绪评估（即，自主神经 系统活动、面部行为和主观体验），如Aβ升高所示 （Aβ+）和tau沉积（110例遗忘/执行障碍AD，45例lvPPA和45例PCA）， 和150名老年健康对照，有和没有AD病理（75 Aβ+和75 Aβ-），tau水平不同 病理通过将情绪测量与临床数据、结构和功能连接、Aβ和tau蛋白 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+健康对照组的社会行为。在目标2中，我们将描述结构和 功能性神经网络在整个AD谱的情绪变化的基础。在目标3中，我们将阐明 Aβ和tau病理学、情绪系统功能和情感症状之间的关联。通过锻造 情绪、神经网络功能障碍、情感症状、Aβ和tau蛋白沉积测量之间的联系， 拟议的研究将有助于拓宽AD最早表现的模型，并阐明如何 特定的神经病理学变化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.