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

非遗忘性轻度认知障碍疾病传播的网络神经科学研究

• 批准号: 10554407
• 负责人: Jeffrey S Phillips
• 金额: $ 12.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554407
• 关键词: Affect; Age; Age of Onset; Alzheimer' s Disease; Amyloid; Anatomy; Area; Atrophic; Binding; Biological; Brain; Brain imaging; Cells; Clinical; Clinical Trials; Cognitive; Computer Models; Coupled; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Disease Progression; Disease model; Ensure; Episodic memory; Evolution; Functional Magnetic Resonance Imaging; Graph; Heterogeneity; Hybrids; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Language; Learning; Measures; Medial; Memory; Memory Loss; Mentorship; Methods; Modeling; Molecular; Neocortex; Neurodegenerative Disorders; Neurons; Neurosciences; Noise; Onset of illness; Participant; Pathogenicity; Pathology; Patients; Pattern; Phenotype; Physiological; Positron-Emission Tomography; Postdoctoral Fellow; Production; Proteins; Regional Disease; Research; Research Personnel; Rest; Rodent; Sampling; Social Behavior; Stratification; Structural Models; Structure; Study models; Symptoms; Syndrome; Temporal Lobe; Testing; Training; Validation; Visuospatial; Work; age effect; amnestic mild cognitive impairment; cell preparation; disease transmission; executive function; experimental study; improved; in vivo; individual patient; insight; longitudinal positron emission tomography; mild cognitive impairment; neocortical; network models; neuroimaging; neurotransmission; patient subsets; predictive modeling; preservation; programs; protein aggregation; radioligand; serial imaging; skills; tau Proteins; translational applications; translational potential; transmission process

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.

项目摘要 阿尔茨海默氏病（AD）的晚期阶段与多种认知的严重损害有关 领域，但早期疾病阶段是异质的，其中一部分患者表现出保留记忆力 结合非烟雾域中的轻度认知障碍（MCI）。虽然这些非武器MCI （NAMCI）患者很少见，他们以多种方式挑战了典型的羊膜MCI的特征。此外 在年轻的年龄显示症状，在新皮层和相对中有更高的tau病理负担 保留内侧颞叶（MTL）。这些差异引起质疑疾病的进展 基于Amnestic MCI和AD的模型可以应用于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层或MTL保护的特定脆弱性。 当前项目将通过将网络神经科学方法应用于 来自NAMCI和Amnescis MCI（AMCI）患者的纵向成像数据。最近的计算建模 AMCI和AD的研究支持了跨神经元传播假设，这提出了有毒 蛋白质通过大脑区域之间的长距离解剖联系以及区域变化而传播 蛋白质聚集和清除率。这些机制中的每一个都通过融合证据支持 从啮齿动物和细胞制剂的实验中，但尚未研究它们在NAMCI中的贡献。 我将使用网络扩散模型评估每种机制的证据，这些模型代表疾病 当电流流过电路时，通过大脑网络传播。我预测这种疾病 NAMCI的进展将与新皮质脆弱性标记有关，包括跨性别的增加 神经元传播和病理的区域产生以及清除率降低。 AD中疾病进展的完整模型必须能够解释异质性 临床医生观察患者的认知障碍和疾病进展率。当前的研究将 通过测试是否认为影响疾病进展的机制来提高这种理解 在Amnestic MCI中可以推广到NAMCI。此外，这项工作将为我提供基本的培训 我从博士后研究过渡到独立研究计划。我将从指导和 网络神经科学和翻译神经影像学，正电子发射断层扫描中的结构化学习 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 知道我通过这项培训获得的知识，我将能够启动一项研究计划，以预测性 通过潜在的翻译应用对神经退行性疾病进展的建模。这项研究是 特别是因为不断努力改善分层和发展临床试验终点。