PDF(Pubmed)
Abstract：
Alzheimer\'s disease may be conceptualized as a \'disconnection syndrome\', characterized by the breakdown of neural connectivity within the brain as a result of amyloid-beta plaques, tau neurofibrillary tangles and other factors leading to progressive degeneration and shrinkage of neurons, along with synaptic dysfunction. It has been suggested that misfolded tau proteins spread through functional connections (known as \'prion-like\' properties of tau). However, the local effect of tau spreading on the synaptic function and communication between regions is not well understood. I aimed to investigate how the spreading of tau aggregates through connections can locally influence functional connectivity. In total, the imaging data of 211 participants including 117 amyloid-beta-negative non-demented and 94 amyloid-beta-positive non-demented participants were recruited from the Alzheimer\'s Disease Neuroimaging Initiative. Furthermore, normative resting-state functional MRI connectomes were used to model tau spreading through functional connections, and functional MRI of the included participants was used to determine the effect of tau spreading on functional connectivity. I found that lower functional connectivity to tau epicentres is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants. Also, amyloid-beta-PET in tau epicentres mediated the association of tau spreading and functional connectivity to epicentres suggesting a partial mediating effect of amyloid-beta deposition in tau epicentres on the local effect of tau spreading on functional connectivity. My findings provide strong support for the notion that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicentre and non-epicentre regions independent of amyloid-beta pathology. Also, I defined several groups based on the relationship between tau spreading and functional disconnection, which provides quantitative assessment to investigate susceptibility or resilience to functional disconnection related to tau spreading. I showed that amyloid-beta, other copathologies and the apolipoprotein E epsilon 4 allele can be a leading factor towards vulnerability to tau relative functional disconnection.
摘要：
阿尔茨海默病可能被概念化为“断线综合征”，其特征是由于β淀粉样蛋白斑块导致大脑内神经连接的破坏，tau神经原纤维缠结和其他因素导致神经元进行性变性和收缩，伴随着突触功能障碍。已经提出错误折叠的tau蛋白通过功能性连接(称为tau的“朊病毒样”特性)传播。然而,tau扩散对突触功能和区域间交流的局部影响尚不清楚。我的目的是研究tau聚集体通过连接的传播如何局部影响功能连接。总的来说,211名参与者的影像学数据包括117名淀粉样β阴性非痴呆和94名淀粉样β阳性非痴呆参与者,均来自阿尔茨海默病神经影像学计划.此外，规范的静息状态功能MRI连接体用于模拟通过功能连接传播的tau，纳入参与者的功能MRI用于确定tau扩散对功能连接的影响.我发现与tau中心的较低功能连接与tau通过淀粉样β阴性和淀粉样β阳性参与者的功能连接传播有关。此外，tau表皮中的淀粉样蛋白-β-PET介导了tau扩散和功能连接与表皮的关联，表明tau表皮中的淀粉样蛋白-β沉积对tau扩散对功能连接的局部作用具有部分介导作用。我的发现为以下观点提供了强有力的支持：tau通过连接传播与tau中心和非中心区域之间的功能连接中断有关，而与β淀粉样蛋白病理学无关。此外，我根据tau传播和功能断开之间的关系定义了几个组，提供定量评估，以调查与tau传播相关的功能断开的易感性或弹性。我发现β淀粉样蛋白,其他共病理学和载脂蛋白Eepsilon4等位基因可能是容易发生tau相对功能断开的主要因素。
