Behavioral and Neural Indicators of Prodromal Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是一种以不可逆的认知障碍为特征的使人衰弱的痴呆形式。 AD诊断历来依赖于识别认知障碍，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出现很长时间后才出现，这一问题就成了问题。 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。 认知症状的表现。神经精神障碍，如睡眠障碍和情绪障碍 在临床前AD患者中很容易观察到这些问题（即冷漠），因此是目标行为问题。 前驱AD的症状毫不奇怪，大脑中调节情绪和睡眠的区域也是大脑中的一个重要区域。 首先检测到AD神经病理学的部位。等枝晶核（IC）是一个相互连接的基团， 脑干核对AD病理高度敏感，可以在AD发病前数年检测到。 在皮质和海马中出现标志性病理（即β-淀粉样蛋白斑，异常tau， 神经纤维缠结）。IC病理学被认为是AD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前驱AD的能力， 行为变化可以映射到早期大脑病理学。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灵长类动物模型。这项建议的第一个目的是 通过给绒猴配备活动监测器来研究昼夜活动，评估神经精神症状 以及呈现情感任务以评估指示冷漠的迟钝情感响应。第二个目的 将使用神经组织学和体视学在脑干组织中寻找AD样病理学， 个体最终的目标是将个体内的行为（即睡眠，情绪反应， 认知下降）和脑（即脑干、海马和皮质病理学）测量以形成特征 的前驱期和临床AD。如果神经精神症状和/或脑干病理是 表明前驱AD，那么我们将在绒猴中看到这些前驱指标， 认知能力下降或皮质或海马中的晚期AD样病理。这些目标的结果将 推进前驱AD的诊断标准，促进靶向治疗的开发。

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.