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

摘要 所有神经退行性疾病的共同特征代表着关键的研究目标。所有内容都遵循一个 特征性，解剖顺序，病变沿功能性神经网络通路扩散。 尽管有这些共性，但每种疾病都具有不同的早期区域脆弱性的解剖模式。 这些特定于疾病的解剖模式通过将注意力集中在最 在人类和模型生物中的相关靶点，并强调需要识别哪些大脑区域 在每种疾病中，退化都是最先的。强有力的证据表明，特定的脑干(BS)核发育 阿尔茨海默病患者皮质前的神经原纤维改变。在FTLD中，早期报告提示BS神经变性，但很少见 研究已经使用TDP-43解决了这个问题。这些信息可能会被证明与早期破译有关 区域脆弱性、解剖进展和可能的非认知症状。我们的长期目标 是提供AD和FTLD-TDP中BS漏洞的综合图景，并将此 了解这些疾病的病因。此应用程序的总体目标是识别 AD和FTLD-TDP中BS的组织病理学和细胞构筑的改变 以网络为基础的方法很好地描述了人脑的特点。我们将研究这些原子核的频率和早期 是否涉及，这些变化是否对称和具有地形梯度，以及哪些临床 表现形式是相关联的。这一建议是基于这样的假设，即选定的BS核是 相互依存并不断参与AD和FTLD-TDP的非常早期阶段。澄清BS的参与 将促进生物标记物的发展，改善诊断临床标准，并建议 治疗靶点。这一假设将通过追求两个具体目标来检验：确定 神经病变的年代学、严重性、相互依存性和症状相关性 AD与健康老年人对照组和FTLD与健康老年人对照组的等树突状核心。这 这种方法是创新的，因为它利用大脑处理成厚厚的组织切片并进行3D重建。 该方法比传统方法具有质量好、速度快、经济等优点。 出色的体视学和免疫组织化学研究。此外，控制小组将由一名 一大批健康难求的老年人。这项提议意义重大，因为它预计将 所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力 治疗。综合的组织病理学和细胞构筑学研究对于理解AD和 FTLD，并将作为正在进行和未来翻译研究的基础。

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.