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

项目摘要 65岁或以上的成年人中每10人中就有1人符合临床诊断，85岁或以上的成年人中每3人中就有1人符合临床诊断 阿尔茨海默病(AD)的标准，使AD成为一种公共健康危机。这些统计数据肯定会是 低估了疾病的总体影响，因为疾病的出现比症状出现早了很多年 在所有情况下。如果没有已知的治疗方法，AD的流行和影响只会随着人口的增加而变得更加可怕 年龄。有效的干预取决于行为和神经生物学标记物的识别 出现在临床前AD。虽然大多数AD研究都集中在学习和记忆力的下降上，但患有AD的人 临床前阿尔茨海默病患者的生理和心理功能的自我意识通常会发生变化 对学习和记忆的任何可察觉的损害。岛叶皮质的变化，这是假定的神经 自我意识的相关性，也在临床前AD中表现出特征。反思自我的行为 因此，意识及其相关的神经生物学底物是重要的潜在研究对象。 和干预。这项拟议的工作将描述这些行为以及神经生物学变化。 高度易处理和可翻译的动物模型，在该模型中，AD相关神经病理的发生可以紧密地 控制住了。我们将把淀粉样β寡聚体(AβOs)引入中年恒河猴的大脑-a 我们已经展示的操作导致了与人类早期阿尔茨海默病一致的神经病理。第一个目标是， 我们将评估自我生理意识(即内感)和自我意识的行为指数的变化。 认知意识(即元认知)。在第二个目标中，我们将描述结构的变化 使用磁共振成像检查脑岛的完整性和功能连通性。在第三个目标中，我们将 检查尸检脑岛以寻找AD病理的已知生物标志物。这项提议的目的一直是 设计使所有实验都可以直接转化为已建立的行为测试和技术 可用于人类患者。拟议中的实验也是为了最大限度地进行培训而设计的。 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.