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

描述（由申请人提供）：所有神经退行性疾病共有的特征代表了关键的研究目标。所有这些都遵循一个特征，解剖顺序，病变沿着功能性神经网络路径扩散。尽管存在这些共性，但每种疾病都具有不同的早期区域易感性解剖模式。这些疾病特异性解剖模式通过将注意力集中在人类和模式生物中最相关的靶标上，并强调需要确定每种疾病中哪个脑区首先退化，从而指导转化研究。强有力的证据表明，特定的脑干（BS）核先于皮层发生神经原纤维改变。在FTLD中，早期报告提示BS神经退行性变，但很少有研究使用TDP-43解决这一问题。这一信息可能被证明与破译早期区域易感性、解剖进展和可能的非认知症状有关。我们的长期目标是提供AD和FTLD-TDP中BS易感性的综合图像，并将这种理解纳入这些疾病的发病机制中。本应用程序的总体目标是通过在具有良好特征的人脑中使用基于全面网络的方法来确定AD和FTLD-TDP的BS组织病理学和细胞结构变化。我们将研究这些核受累的频率和早期，变化是否对称和具有地形梯度，以及哪些临床表现与之相关。这一建议是基于这样的假设，即选定的BS核相互依赖并持续参与AD和FTLD-TDP的早期阶段。阐明BS与这些疾病的关系将促进生物标志物的发展，提高临床诊断标准，并提出治疗靶点。该假设将通过追求两个特定目标进行检验：确定AD与健康老年人对照和FTLD与健康老年人对照中等树突核心神经病理变化的时间顺序、严重程度、相互依赖性和症状相关性。这种方法是创新的，因为它利用大脑加工成厚的组织学切片和3D重建。与传统方法相比，该方法质量好，速度快，经济实惠，具有良好的体视学和免疫组化研究效果。此外，对照组将由大量难以获得健康的老年人组成。这一建议意义重大，因为预计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在的治疗方法。综合组织病理学和细胞结构学研究仍然是理解AD和FTLD的关键，并将作为正在进行和未来的转化研究的基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public heath because the high economic and social costs associated with neurodegenerative dementias may soon become an unbearable burden to society and effective disease- modifying treatments remain elusive. For this reason, closing important gaps in the understanding of dementia etiopathogenesis as proposed in this proposal by clarifying the involvement of BS nuclei in AD and FTLD-TDP and proposing novel targets for prevention and treatment of these devastating diseases are relevant to the NIH's mission of reducing burdens of illness and disability.