Brainstem as an early site in AD and FTLD: closing the etiopathogenic gap

摘要 所有神经退行性疾病共有的特征代表了关键的研究目标。都遵循 特征性的解剖序列，病变沿沿着功能性神经网络通路扩散。 尽管有这些共性，每种疾病的特点是一个独特的解剖模式的早期区域脆弱性。 这些疾病特异性解剖模式通过将注意力集中在最重要的方面来指导转化研究。 在人类和模型生物的相关目标，并强调需要确定哪些大脑区域， 在每种疾病中首先退化。强有力的证据表明，特定的脑干（BS）核团的发展 AD时神经元的变化先于皮质。在FTLD中，早期报告提示BS神经退行性变，但很少 研究已经使用TDP-43解决了这个问题。这些信息可能证明与早期破译有关 局部脆弱性、解剖学进展和可能的非认知神经病学。我们的长期目标 是提供AD和FTLD-TDP中BS漏洞的综合情况，并将其 了解这些疾病的发病机制。本申请的总体目标是确定 AD和FTLD-TDP的BS组织病理学和细胞结构变化， 基于网络的方法在良好表征的人类大脑中。我们将研究这些细胞核 是否涉及，变化是否对称，是否有地形梯度，以及哪些临床 表现是相关联的。该建议基于这样的假设，即选择的BS核是 在AD和FTLD-TDP的非常早期阶段相互依赖和不断参与。澄清BS的参与 在这些疾病中的应用将促进生物标志物的开发，改善诊断临床标准，并建议 治疗目标该假设将通过追求两个具体目标进行测试： 神经病理学变化的时间顺序、严重程度、相互依赖性和神经病理学相关性 在AD与健康老年人对照和FTLD与健康老年人对照中的等树突核心。这 这种方法是创新的，因为它利用大脑处理成厚的组织学切片和3D重建。 该方法比传统方法具有质量上级、快速、经济等优点， 体视学和免疫组织化学研究。此外，对照组将由 大量健康老人难觅。这一建议意义重大，因为预计 获得的知识将突出未被识别的早期症状，并提出新的生物标志物和潜在的 治疗组织病理学和细胞结构学的综合研究对于理解AD和 FTLD将作为正在进行的和未来的转化研究的基础。

Abstract Features shared by all neurodegenerative diseases represent critical research targets. All follow a characteristic, anatomical sequence, with lesions that spread along functional neuronal network pathways. Despite these commonalities, each disease features a distinct anatomical pattern of early regional vulnerability. These disease-specific anatomical patterns guide translational research by focusing attention on the most relevant targets in humans and model organisms and emphasize the need to identify which brain areas degenerate first in each disease. Strong evidences suggest that specific brainstem (BS) nuclei develop neurofibrillary changes before the cortex in AD. In FTLD, early reports suggest BS neurodegeneration, but few studies have addressed this issue using TDP-43. This information may prove relevant for deciphering early regional vulnerability, anatomical progression and possible non- cognitive symptomatology. Our long-term goal is to provide an integrated picture of BS vulnerability in AD and FTLD-TDP and to incorporate this understanding into the etiopathogenesis of these diseases. The overall objective of this application is to identify the BS histopathological and cytoarchitectonic changes in AD and FTLD-TDP by using a comprehensive network-based approach in well characterized human brains. We will study how often and early these nuclei are involved, whether the changes are symmetric and have a topographical gradient, and which clinical manifestations are associated. This proposal is based on the hypothesis that selected BS nuclei are interdependently and constantly involved in very early stages of AD and FTLD-TDP. Clarifying BS involvement in these diseases will facilitate development of biomarkers, improve diagnostic clinical criteria, and suggest therapeutic targets. The hypothesis will be tested by pursuing two specific aims: To determine the chronology, severity, interdependence, and symptom-relevance of neuropathological changes in the isodendritic core in AD vs. healthy elderly controls and in FTLD vs. healthy elderly controls. This approach is innovative because it utilizes brains processed into thick histological slides and 3D reconstructed. This method is superior in quality, quicker and more economical than the traditional methods and renders excellent stereological and immunohistochemical studies. In addition, the control groups will be composed of a large number of difficult-to-get healthy elderly. This proposal is significant because it is expected to that the knowledge gained will highlight unrecognized early symptoms and suggest new biomarkers and potential therapies. Integrative histopathological and cytoarchitectonic studies remain critical to understanding AD and FTLD and will serve as a foundation for ongoing and future translational research.