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

项目总结 晚期阿尔茨海默病(AD)与多种认知功能严重受损有关 领域，但早期疾病阶段是不同的，患者的子集显示保存的记忆 合并非遗忘症领域的轻度认知障碍(MCI)。尽管这些非遗忘型的MCI (NAMCI)患者很罕见，他们以多种方式挑战典型的遗忘性MCI的特征。除了……之外 在较年轻的时候出现症状，他们在新皮质和亲属的tau病理负担更高。 保留内侧颞叶(MTL)。这些差异令人怀疑疾病的进展 基于遗忘MCI和AD的模型可以应用于NAMCI。此外，目前还不清楚是否 在NAMCI中观察到的新皮质疾病反映了新皮质的特殊脆弱性或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 NAMCI和遗忘型MCI(AMCI)患者的纵向成像数据。最新的计算建模 对aMCI和AD的研究支持了跨神经元传递假说，该假说认为 蛋白质通过大脑区域之间的远距离解剖连接以及区域变化进行传播 蛋白质的聚集率和清除率。这些机制中的每一种都得到了证据的支持 来自啮齿动物和细胞制剂的实验，但它们在NAMCI中的贡献尚未被调查。 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，就像电流流经电路一样。我预言了这种疾病 NAMCI的进展将与新皮质易损性的标志有关，包括反式-MCI增加 神经元传递和局部病理产生以及清除减少。 一个完整的AD疾病发展模型必须能够解释这种异质性 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来推动这一理解 在遗忘症中，MCI可推广到NAMCI。此外，这项工作将为我提供必要的培训，因为 我从博士后研究过渡到独立研究项目。我将受益于导师和 网络神经科学中的结构化学习和翻译神经成像，正电子发射断层扫描 成像，以及神经退行性疾病的生物学基础。通过将技能和特定领域的 我通过这次培训获得的知识，我将能够启动一个专注于预测的研究计划 神经退行性疾病进展的模型及其潜在的翻译应用。这项研究是 尤其及时，因为正在努力改进分层和开发临床试验终点。

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.