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: 9910342
• 负责人: Emily S. Rothwell
• 金额: $ 6.12万
• 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/9910342
• 关键词: Affect; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; 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; Patients; 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; disease diagnosis; experimental study; heart rate variability; in vivo; locus ceruleus structure; neuropathology; neuropsychiatric disorder; neuropsychiatric symptom; nonhuman primate; parent grant; pre-clinical; 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.

项目摘要 阿尔茨海默氏病（AD）是痴呆症的一种使人衰弱的形式，其特征是不可逆的认知障碍。 AD诊断在历史上放松了识别认知障碍，但该诊断标准已成为 有问题随着证据表明神经病理学结束很长时间存在的认知症状。 临床前阶段诊断AD对于开发新的治疗方法至关重要 认知症状的表现。神经精神疾病，例如睡眠障碍和情感障碍 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 前驱AD的症状。毫不奇怪，调节情绪和睡眠的大脑区域也是 首先检测到AD神经病理学的部位。 iSodendritic Core（IC）是一组相互联系的组 脑干核非常容易受到AD病理的影响，可以在几年之前检测到 标志性病理在皮质和海马中的出现（即β-淀粉样斑块，异常Tau， 神经纤维缠结）。提出了IC病理学的基础，包括AD的前驱症状，包括冷漠和 睡眠障碍。动物模型可以提高识别和诊断前驱广告的能力，因为 行为改变可以映射到早期的脑病理上。该提议将研究老化的果moset 猴子，是研究神经认知衰老的理想非人类私人模型。该提议的第一个目的是 通过与活动监测器一起拟合摩尔果素来研究昼夜节律活动来评估神经精神症状 并提出一项情感上的任务，以评估表明冷漠的情绪反应。第二个目标 将使用神经组织学和立体学来寻找来自同一组织的脑干组织中的广告样病理学 个人。最终目标将融合个体内部行为（即睡眠，情感反应， 认知能力下降）和大脑（即脑干，海马和皮质病理学）措施发展特征 果果中前驱和临床广告。如果神经精神症状和/或脑干病理是 指示前驱AD的指示，然后我们将在没有显着意义的桃花子中看到这些前驱指标 皮质或海马的认知能力下降或晚期类似AD样病理。这些目标的结果将 前驱AD的提前诊断标准和支持有针对性的治疗开发。