Brain network dependent propagation of tau-pathology in Alzheimer disease

阿尔茨海默病中 tau 病理学的脑网络依赖性传播

• 批准号: 329109473
• 负责人: Professor Dr. Alexander Drzezga
• 金额: --
• 依托单位: Max-Planck-Institut für Stoffwechselforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/329109473?language=en
• 关键词: Brain; network; dependent; propagation; tau

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.

在阿尔茨海默氏病中，蛋白质聚集的两种主要形式，被视为疾病的潜在因子，是β-淀粉样蛋白（淀粉样蛋白 - plaques）的细胞外沉积物和tau-蛋白质蛋白（神经纤维纤维缠结）的细胞内聚集物。在过去的几年中，关于阿尔茨海默氏病的研究一直集中在淀粉样病理学上。然而，最近，tau - 聚集病理正在进入注意力的重点，尤其是旨在减少淀粉样蛋白 - 聚集病理学的众多临床试验尚未显示出突破性的成功。已经提出，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/进展更加紧密。 在所谓的网络变性假设的背景下，tau - 病理学在发病机理中的关键作用似乎特别合理。今天引入功能性MRI（RSFMRI）静止状态连接分析允许识别大脑中功能连接网络。网络退化假设表明，神经退行性的扩展遵循大脑的特定功能连接网络。最近的发现表明，类似王子的机制可能与tau-Phatogy的传播有关。已经表明，tau凝集物似乎能够反式突触扩散，即从一个特定受影响的神经元的突触末端泄漏，穿过突触裂缝，并有可能在随后的连接神经元中进一步诱导tau蛋白的进一步聚集。 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.正电子发射断层扫描（PET）的新型分子成像示踪剂可在体内测量tau凝集物，这可能非常适合于这种科学目的。因此，在当前的研究中，我们将在阿尔茨海默氏病的受试者中应用多模式成像方案，包括RSFMRI，淀粉样蛋白PET和TAU-PET，并在纵向方法中有风险的受试者，以解决以下假设：1。 tau-PATHOLOGY沿着大脑的神经元网络扩展。 2。tau病理学的扩展导致受影响网络和连续网络特定认知能力下降的逐渐障碍。3。使用基线TAU沉积，淀粉样蛋白沉积和网络结构的数学模型，随着时间的流逝，TAU病理的进展可以预测。