Brain network dependent propagation of tau-pathology in Alzheimer disease

在阿尔茨海默病中，两种主要的蛋白质聚集形式被认为是疾病的潜在原因，即细胞外β -淀粉样蛋白沉积（淀粉样斑块）和细胞内tau蛋白聚集（神经原纤维缠结）。在过去的几年里，对阿尔茨海默病的研究一直集中在淀粉样蛋白病理学上。然而，最近，tau聚集病理正成为人们关注的焦点，特别是许多旨在减少淀粉样蛋白聚集病理的临床试验尚未取得突破性的成功。与淀粉样蛋白相比，大脑中tau沉积的程度与认知障碍的程度/进展更密切相关。在所谓的网络退化假说的背景下，tau病理在发病机制中的关键作用似乎特别合理。功能磁共振成像（rsfMRI）静息状态连通性分析的引入今天允许识别大脑中的功能连接网络。网络退行性变假说认为，神经退行性变的扩展遵循整个大脑的特定功能连接网络。最近的研究结果表明，一种类似朊病毒的机制可能参与了tau病理的传播。研究表明，tau蛋白聚集物似乎能够跨突触扩散，即从一个特定受影响神经元的突触末端泄漏出来，穿过突触间隙，并可能在随后连接的神经元中诱导tau蛋白的进一步聚集。这一发现可以解释为什么神经退行性病理可能显示出一种扩展模式，遵循整个大脑的功能连接途径。因此，随着时间的推移，研究tau聚集物在体内的沉积及其与其他神经退行性病理和大脑功能网络的关系具有重要的科学意义，可能有助于理解阿尔茨海默病发展的病理生理机制。用于正电子发射断层扫描（PET）的新型分子成像示踪剂可以测量体内的tau聚集体，可能非常适合服务于这一科学目的。因此，在当前的研究中，我们将采用包括rsfMRI、淀粉样蛋白pet和tau-PET在内的多模态成像方案，对阿尔茨海默病患者和高危人群进行纵向研究，以解决以下假设：tau病理学沿着大脑的神经网络扩展。2. 这种tau病理扩展导致受影响网络的进行性功能损伤和连续的网络特异性认知衰退。利用整合基线tau沉积、淀粉样蛋白沉积和网络结构的数学模型，可以在个体患者中预测tau病理随时间的进展。

In Alzheimer disease, two major forms of protein aggregation, discussed as potential causal factors of disease, are the extracellular deposits of beta-amyloid (amyloid-plaques) and the intracellular aggregates of tau-protein (neurofibrillary tangles). In the past years, research on Alzheimer disease has been has been strongly focused on amyloid-pathology. However, more recently, tau-aggregation pathology is moving into the focus of attention, particularly as numerous clinical trials aiming to reduce amyloid-aggregation pathology have not shown ground-breaking success. It has been suggested that the extent of tau-deposition in the brain correlates more closely to the degree/progression of cognitive impairment as compared to amyloid. A key role of tau-pathology in the pathogenesis appears particularly plausible in the context of the so-called network degeneration hypothesis. The introduction of functional MRI (rsfMRI) resting state connectivity analysis today allows the identification of functional connectivity networks in the brain. The network degeneration hypothesis suggests that the expansion of neurodegeneration follows specific functional connectivity networks across the brain. Recent findings indicate that a prion-like mechanism may be involved in the spreading of tau-pathology. It has been shown that tau-aggregates appear to be capable of trans-synaptic spreading, i.e. to leak out of the synaptic terminal of one specific affected neuron, cross the synaptic cleft and potentially induce further aggregation of tau-proteins in the subsequent connected neuron. This finding would explain why neurodegenerative pathology may show an expansion pattern following functional connectivity pathways across the brain.Consequently, the investigation of deposition of tau-aggregates in vivo over time and its relation to other neurodegenerative pathologies and the functional networks of the brain is of major scientific interest and may aid significantly in the understanding of pathophysiological mechanisms involved in development of Alzheimer disease. Novel molecular imaging tracers for Positron Emission Tomography (PET) allowing to measure tau-aggregates in vivo may be ideally suited to serve this scientific purpose. Thus, in the current study, we will apply a multimodal imaging protocol including rsfMRI, amyloid-PET and tau-PET in subjects with Alzheimer disease and subjects at risk in a longitudinal approach, to address the following hypotheses:1. Tau-pathology expands along neuronal networks of the brain. 2. This expansion of tau pathology leads to progressive functional impairment of affected networks and consecutive network-specific cognitive decline.3. Using a mathematical model integrating baseline tau deposition, amyloid deposition and network architecture, the progression of tau pathology over time can be predicted in the individual patient.