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

脑干作为 AD 和 FTLD 的早期部位：缩小病因差距

• 批准号: 8245592
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 45.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245592
• 关键词: Address; Affect; Alzheimer' s Disease; Animal Model; Area; Attention; Biological Markers; Brain; Brain Stem; Cell Nucleus; Characteristics; Chronology; Clinical; Cognitive; Complement; Control Groups; Data; Dementia; Development; Diagnosis; Diagnostic; Disease; Economics; Elderly; Foundations; Frontotemporal Lobar Degenerations; Future; Goals; Human; Individual; Injury; Knowledge; Lesion; Methods; Midbrain structure; Mission; Nerve Degeneration; Network-based; Neurobiology; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Patients; Pattern; Phase; Physiological Processes; Prevention; Process; Proteins; Reporting; Research; Severities; Site; Slide; Societies; Staging; Stereotyping; Structure; Substantia nigra structure; Supratentorial; Symptoms; Targeted Research; Testing; Thick; Translational Research; Work; base; burden of illness; cost; disability; dorsal motor nucleus; dorsal raphe nucleus; entorhinal cortex; improved; innovation; neurodegenerative dementia; neuron loss; new therapeutic target; novel; preference; protein TDP-43; social; spatiotemporal; tau Proteins; therapeutic target

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.

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人类和模型生物中最相关的靶点上来指导转化研究，并强调需要确定每种疾病中哪些大脑区域首先退化。强有力的证据表明，特定的脑干（BS）核团在AD的皮质之前发生神经元性变化。在FTLD中，早期报告表明BS神经变性，但很少有研究使用TDP-43解决这个问题。这些信息可能与破译早期区域脆弱性、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脆弱性的综合图片，并将这种理解纳入这些疾病的发病机制。本申请的总体目标是通过在充分表征的人脑中使用基于网络的综合方法来识别AD和FTLD-TDP中的BS组织病理学和细胞结构变化。我们将研究这些核团受累的频率和早期，这些变化是否对称，是否有地形梯度，以及哪些临床表现相关。该建议是基于这样的假设，即所选择的BS核相互依赖地并且不断地参与AD和FTLD-TDP的非常早期的阶段。阐明BS参与这些疾病将促进生物标志物的发展，改善诊断临床标准，并建议治疗靶点。将通过追求两个特定目标来检验该假设：确定AD与健康老年对照组和FTLD与健康老年对照组中等树突核心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。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。该方法具有上级、快速、经济、体视学和免疫组化研究效果好等优点。此外，对照组将由大量的难以获得的健康老人组成。这一提议意义重大，因为预计获得的知识将突出未识别的早期症状，并提出新的生物标志物和潜在的治疗方法。整合的组织病理学和细胞结构研究对于理解AD和FTLD仍然至关重要，并将作为正在进行和未来的转化研究的基础。 公共卫生关系：拟议的研究与公共卫生有关，因为与神经退行性痴呆相关的高经济和社会成本可能很快成为社会无法承受的负担，有效的疾病改善治疗仍然难以实现。因此，通过澄清BS核在AD和FTLD-TDP中的参与并提出预防和治疗这些毁灭性疾病的新靶点，弥合本提案中提出的对痴呆发病机制的理解方面的重要差距，与NIH减轻疾病和残疾负担的使命相关。