Behavioral and Neural Indicators of Prodromal Alzheimer's Disease

项目摘要 阿尔茨海默病(AD)是一种以不可逆转的认知损害为特征的衰弱形式的痴呆症。 AD诊断历史上依赖于识别认知功能障碍，但这一诊断标准已成为 随着越来越多的证据表明认知症状在神经病理学开始很久之后就出现了，这是有问题的。 在临床前阶段诊断AD对于开发新的治疗方法以在AD发生之前进行干预至关重要 出现认知症状。神经精神障碍，如睡眠障碍和情绪障碍 问题(即冷漠)很容易在临床前AD患者中观察到，因此是目标行为 前驱阿尔茨海默病症状。毫不奇怪，大脑中调节情绪和睡眠的区域也是 首次发现阿尔茨海默病神经病理的部位。等树状核(IC)是一组相互连接的 对AD病理高度敏感的脑干核团，可以在AD发病前几年被检测到 皮质和海马区出现显著的病理改变(如β-淀粉样斑块、异常tau、 神经原纤维缠结)。IC病理学被认为是AD的前驱症状的基础，包括冷漠和 睡眠障碍。动物模型提高了识别和诊断先兆AD的能力，因为 行为变化可以映射到早期的大脑病理。这项提案将研究老化的绒猴 猴子是研究神经认知老化的理想非人类灵长类动物模型。这项建议的第一个目的是 通过为绒猴配备活动监测器来研究昼夜活动来评估神经精神症状 并提出了一项情绪任务，以评估迟钝的情绪反应，表明冷漠。第二个目标 将使用神经组织学和体视学在相同的脑干组织中寻找AD样病理 个人。最终目标将把个体内部的行为(即睡眠、情绪反应、 认知功能减退)和大脑(即脑干、海马体和大脑皮层病理)的方法来形成侧写 绒猴的前驱症状和临床AD的关系。如果神经精神症状和/或脑干病理 我们将在绒猴身上看到这些前驱指标，而没有显著的 大脑皮质或海马区出现认知功能减退或进展性AD样病变。这些目标的结果将是 提高先兆AD的诊断标准，促进靶向治疗的发展。

Project Summary Alzheimer's Disease (AD) is a debilitating form of dementia characterized by irreversible cognitive impairment. AD diagnosis historically relied on identifying cognitive impairment but this diagnostic criterion has become problematic as evidence grows that cognitive symptoms present long after neuropathology has set in. Diagnosing AD in the preclinical stages is critical to develop new treatments to intervene prior to the presentation of cognitive symptoms. Neuropsychiatric disorders, such as sleep impairments and emotional problems (i.e. apathy), are readily observed in preclinical AD patients and therefore are target behavioral symptoms for prodromal AD. Not surprisingly, the brain regions that regulate emotion and sleep are also the sites where AD neuropathology is first detected. The isodendritic core (IC) is an interconnected group of brainstem nuclei that are highly susceptible to AD pathology, which can be detected years before the emergence of hallmark pathology in the cortex and hippocampus (i.e. β-amyloid plaques, abnormal tau, neurofibrillary tangles). IC pathology is proposed to underlie prodromal symptoms of AD, including apathy and sleep disturbances. Animal models advance the ability to recognize and diagnose prodromal AD because behavioral changes can be mapped onto early brain pathology. This proposal will study aging marmoset monkeys, an ideal nonhuman primate model to study neurocognitive aging. The first aim of this proposal is to evaluate neuropsychiatric symptoms by outfitting marmosets with activity monitors to study circadian activity and presenting an emotion task to evaluate blunted emotional responding indicative of apathy. The second aim will use neurohistology and stereology to look for AD-like pathology in brainstem tissues from the same individuals. The final aim will draw together within-individual behavioral (i.e. sleep, emotion responding, cognitive decline) and brain (i.e. brainstem, hippocampal and cortical pathology) measures to develop profiles of prodromal and clinical AD in marmosets. If neuropsychiatric symptoms and/or brainstem pathology are indicative of prodromal AD, then we will see these prodromal indicators in marmosets without significant cognitive decline or advanced AD-like pathology in the cortex or hippocampus. The results from these aims will advance diagnostic criteria for prodromal AD and facilitate targeted treatment development.