A Network Neuroscience Investigation of Disease Spread in Non-Amnestic Mild Cognitive Impairment

项目摘要 阿尔茨海默病（AD）的晚期与多种认知功能的严重损害有关， 领域，但早期疾病阶段是异质性的，一部分患者显示出保留的记忆 合并非遗忘领域的轻度认知障碍（MCI）。虽然这些非遗忘型MCI （naMCI）患者是罕见的，他们以多种方式挑战典型遗忘型MCI的特征。除了 在年轻时显示症状，他们在新皮层和相对皮层中具有更高的tau病理学负担。 保留内侧颞叶（MTL）。这些差异引发了一个问题，即疾病进展是否 基于遗忘MCI和AD的模型可应用于naMCI。此外，尚不清楚是否 在naMCI中观察到的新皮质疾病反映了新皮质的特定脆弱性或MTL的保护。 目前的项目将通过应用网络神经科学方法来研究这些问题， 来自naMCI和遗忘型MCI（aMCI）患者的纵向成像数据。最近的计算模型 对aMCI和AD的研究支持了跨神经元传递假说，该假说提出， 蛋白质通过大脑区域之间的长距离解剖连接以及区域变化传播 蛋白质聚集和清除的速率。这些机制中的每一个都得到了汇聚证据的支持 从啮齿动物和细胞制剂的实验，但他们在naMCI的贡献还没有被调查。 我将使用代表疾病的网络扩散模型来评估每种机制的证据 通过大脑网络传播，就像电流流过电路一样。我预测这种疾病 naMCI的进展将与新皮质脆弱性的标志物相关，包括跨- 神经元传递和病理学的区域产生以及清除率降低。 AD疾病进展的完整模型必须能够解释 临床医生观察患者的认知障碍和疾病进展率。目前的研究将 通过测试被认为影响疾病进展的机制， 在遗忘型MCI中，可以概括为naMCI。此外，这项工作将为我提供必要的培训， 我从博士后研究过渡到独立的研究项目。我将受益于导师制， 网络神经科学中的结构化学习和转化神经成像，正电子发射断层扫描 成像和神经退行性疾病的生物学基础。通过整合技能和特定领域 我通过这次培训获得的知识，我将能够启动一项专注于预测的研究计划 具有潜在转化应用的神经退行性疾病进展的建模。本研究是 由于正在努力改进分层和制定临床试验终点，因此特别及时。

PROJECT SUMMARY The advanced stages of Alzheimer's disease (AD) are associated with severe impairment in multiple cognitive domains, but early disease stages are heterogeneous, with a subset of patients displaying preserved memory combined with mild cognitive impairment (MCI) in non-amnestic domains. Although these non-amnestic MCI (naMCI) patients are rare, they challenge the profile of typical amnestic MCI in multiple ways. In addition to showing symptoms at a younger age, they have a higher burden of tau pathology in the neocortex and relative sparing of the medial temporal lobes (MTL). These differences call into question whether disease progression models based on amnestic MCI and AD can be applied to naMCI. Furthermore, it remains unclear whether neocortical disease observed in naMCI reflects specific vulnerability of the neocortex or protection of the MTL. The current project will investigate these questions by applying network neuroscience approaches to longitudinal imaging data from naMCI and amnestic MCI (aMCI) patients. Recent computational modeling studies in aMCI and AD have supported the trans-neuronal transmission hypothesis, which proposes that toxic proteins propagate via long-distance anatomical connections between brain areas, as well as regional changes in rates of protein aggregation and clearance. Each of these mechanisms is supported by converging evidence from experiments in rodents and cell preparations, but their contributions in naMCI have not been investigated. I will evaluate the evidence for each mechanism using network diffusion models, which represent disease spread through brain networks much as electric current flows through a circuit. I predict that disease progression in naMCI will be associated with markers of neocortical vulnerability, including increases in trans- neuronal transmission and regional production of pathology as well as decreased clearance. A complete model of disease progression in AD must be able to explain the heterogeneity that clinicians observe in patients' cognitive impairment and rates of disease progression. The current research will advance this understanding by testing whether mechanisms that are thought to influence disease progression in amnestic MCI can be generalized to naMCI. Furthermore, this work will provide me with essential training as I transition from postdoctoral research to an independent research program. I will benefit from mentorship and structured learning in network neuroscience and translational neuroimaging, positron emission tomography imaging, and the biological basis of neurodegenerative disease. By integrating the skills and domain-specific knowledge that I gain through this training, I will be able to launch a program of research focusing on predictive modeling of neurodegenerative disease progression with potential translational application. This research is particularly timely because of ongoing efforts to improve stratification and develop clinical trial end-points.