Behavioral and Neural Indicators of Prodromal Alzheimer's Disease

阿尔茨海默病前驱期的行为和神经指标

• 批准号: 10056168
• 负责人: Emily S. Rothwell
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056168
• 关键词: Affect; Aging; Alzheimer disease detection; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animal Model; Basal Nucleus of Meynert; Behavioral; Behavioral Symptoms; Brain; Brain Pathology; Brain Stem; Brain region; Callithrix; Callithrix jacchus jacchus; Cell Nucleus; Circadian Rhythms; Clinical; Cognitive aging; Data; Databases; Dementia; Development; Diagnosis; Diagnostic; Diffuse; Disease Progression; Dorsal; Early Diagnosis; Early Intervention; Emotional; Emotions; Etiology; Evaluation; Face; Fellowship; Future; Grant; Heart Rate; Hippocampus (Brain); Human; Image; Immunohistochemistry; Impaired cognition; Individual; Intervention; Longevity; Longitudinal Studies; Maps; Measurement; Measures; Mental Depression; Modeling; Monitor; Monkeys; Neurobehavioral Manifestations; Neurocognitive; Neurodegenerative Disorders; Pathology; Pattern; Peripheral; Physiology; Population; Prevalence; Research; Rest; Senile Plaques; Severities; Site; Sleep; Sleep disturbances; Staging; Stains; Stimulus; Substantia nigra structure; Symptoms; Temperature; Therapeutic Intervention; Tissues; Training; Tyrosine 3-Monooxygenase; World Health Organization; aged; basal forebrain; behavioral study; circadian; cognitive task; experimental study; heart rate variability; human old age (65+); in vivo; locus ceruleus structure; neuropathology; neuropsychiatric disorder; neuropsychiatric symptom; nonhuman primate; parent grant; pre-clinical; prodromal Alzheimer' s disease; relating to nervous system; response; sleep pattern; targeted treatment; tau aggregation; tau mutation; therapy development

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.

项目概要 阿尔茨海默病 (AD) 是一种使人衰弱的痴呆症，其特征是不可逆的认知障碍。 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久之后才出现，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 认知症状的表现。神经精神疾病，例如睡眠障碍和情绪障碍 问题（即冷漠）在临床前 AD 患者中很容易观察到，因此是目标行为 AD 前驱症状。毫不奇怪，调节情绪和睡眠的大脑区域也是 AD 神经病理学首次发现的部位。等枝晶核心 (IC) 是一组相互连接的 脑干细胞核对 AD 病理非常敏感，可以在 AD 发病前数年就被检测到 皮质和海马出现标志性病理（即 β-淀粉样斑块、异常 tau 蛋白、 神经原纤维缠结）。 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，因为 行为变化可以映射到早期大脑病理学。该提案将研究衰老狨猴 猴子是研究神经认知衰老的理想非人类灵长类动物模型。该提案的首要目标是 通过为狨猴配备活动监视器来研究昼夜节律活动来评估神经精神症状 并提出一项情绪任务来评估表明冷漠的迟钝情绪反应。第二个目标 将使用神经组织学和体视学来寻找来自同一区域的脑干组织中类似 AD 的病理学 个人。最终目标将汇集个人内部行为（即睡眠、情绪反应、 认知能力下降）和大脑（即脑干、海马和皮质病理学）测量以开发概况 狨猴的前驱期和临床 AD 的研究。如果神经精神症状和/或脑干病理学是 指示前驱 AD，那么我们将在狨猴中看到这些前驱指标，但没有显着 认知能力下降或皮质或海马体出现晚期 AD 样病理。这些目标的结果将 推进 AD 前驱诊断标准并促进针对性治疗的开发。