Insula Structure and Function in a Nonhuman Primate Model of Induced Early Alzheimer's Disease

项目摘要 每10名65岁或以上的成年人中就有1名，每3名85岁或以上的成年人中就有1名符合临床诊断标准。 阿尔茨海默病（AD）的标准，使AD成为公共卫生危机。这些统计数据肯定是 低估了疾病的总影响，因为疾病的发病先于症状的出现多年 在所有情况下。由于没有已知的治疗方法，随着人口的增加，AD的患病率和影响只会变得更加可怕。 年龄有效的干预取决于行为和神经生物学标志物的识别， 出现在临床前AD中。虽然大多数AD研究都集中在学习和记忆的下降上，但患有AD的人 临床前AD患者的生理和心理功能的自我意识通常会发生变化， 任何可检测到的学习和记忆障碍。岛叶皮层的变化， 与自我意识相关，也已在临床前AD中表征。自我反思的行为 因此，意识及其相关的神经生物学基质是重要的潜在研究目标 和干预。拟议的工作将描述这些行为以及神经生物学变化， 高度易处理和转化的动物模型，其中AD相关的神经病理学的发作可以紧密地 控制。我们将β淀粉样蛋白低聚物（AβOs）引入中年恒河猴的大脑中， 我们已经证明，这种操纵导致的神经病理学与人类早期AD一致。在第一个目标中， 我们将评估生理学的自我意识的行为指数的变化（即，内感受）和自我- 认知的意识（即，元认知）。在第二个目标中，我们将描述结构性变化的特征， 完整性和功能连接性。第三个目标，我们将 检查尸体的AD病理学的已知生物标志物。这项建议的目的是 设计成所有实验都能直接转化为既定的行为测试和技术 可用于人类患者。拟议的实验也被设计为最大限度地提高培训 在行为、成像、组织学和统计技术方面的潜力。

Project Summary One in 10 adults who are aged 65 or older and 1 in 3 adults who are aged 85 or older meet the clinical diagnostic criteria for Alzheimer’s disease (AD), making AD a public health crisis. These statistics are certain to be underestimates of the disease’s total impact, given that disease onset precedes symptom onset by many years in all cases. With no known cure, the prevalence and impact of AD will only become more dire as the population ages. Effective intervention is contingent on the identification of behavioral and neurobiological markers that appear in preclinical AD. While most AD research has focused on declines in learning and memory, people with preclinical AD often have changes to their self-awareness of both physiological and psychological functions prior to any detectable impairments to learning and memory. Changes to the insular cortex, the putative neural correlate of self-awareness, have also been characterized in preclinical AD. Behaviors reflective of self- awareness, and their associated neurobiological substrates, are therefore important potential targets of study and intervention. The proposed work will characterize these behaviors alongside neurobiological changes in a highly tractable and translational animal model, where the onset of AD-related neuropathology can be tightly controlled. We will introduce amyloid beta oligomers (AβOs) into the brains of middle-aged rhesus monkeys—a manipulation that we have shown causes neuropathology consistent with early AD in humans. In the first aim, we will assess changes to behavioral indices of self-awareness of physiology (i.e., interoception) and self- awareness of cognition (i.e., metacognition). In the second aim, we will characterize changes to the structural integrity and functional connectivity of the insula using magnetic resonance imaging. In the third aim, we will examine the insula postmortem for known biomarkers of AD pathology. The aims of this proposal have been designed such that all experiments have direct translation to established behavioral tests and techniques available for use with human patients. The proposed experiments have also been designed to maximize training potential in behavioral, imaging, histological, and statistical techniques.