Characterizing TDP-43 related hippocampal degeneration and memory loss in aging

表征衰老过程中 TDP-43 相关海马变性和记忆丧失

• 批准号: 10376871
• 负责人: JULIE A. SCHNEIDER
• 金额: $ 137.24万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376871
• 关键词: Accounting; Adopted; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Anterior; Astrocytes; Autopsy; Awareness; Behavioral; Blood Vessels; Brain; Cessation of life; Characteristics; Clinical; Cognitive; Communities; Data; Dementia; Diagnosis; Disease; Elderly; Encephalopathies; Enrollment; Frontotemporal Lobar Degenerations; Gliosis; Goals; Hippocampus (Brain); Image; Impaired cognition; Impairment; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory Loss; Microglia; Morphology; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Nomenclature; Pathologic; Pathology; Pattern; Persons; Phenotype; Prevention; Public Health; Research; Resources; Risk; Risk Factors; Role; Scanning; Shapes; Symptoms; Syndrome; Testing; Translating; age related; cognitive change; cohort; density; episodic memory impairment; ex vivo imaging; follow-up; genetic variant; hippocampal sclerosis; in vivo; in vivo imaging; literacy; neurobehavior; neurobehavioral; neuron loss; neuropathology; normal aging; pathology imaging; protein TDP-43; resilience; shape analysis; symposium; tool

PROJECT SUMMARY/ABSTRACT TDP has emerged as an important and common age-related pathology related to the Alzheimer’s clinical syndrome. TDP pathology is found in large number of older brains and is strongly and independently related to episodic memory impairment. TDP pathology occurs in “normal aging,” with and without concomitant Alzheimer’s disease (AD) pathology, and as a primary component hippocampal sclerosis (HS). The clinical syndrome associated with TDP pathology mimics and worsens the Alzheimer’s clinical syndrome. TDP (with and without HS) pathology commonly occurs with AD as mixed pathology and lowers the threshold for dementia (lowers resilience). TDP also occurs in the absence of a pathologic diagnosis of AD and therein is separately associated with memory loss and a dementia that mimics AD. Emerging data suggest that TDP pathology has a large public health impact. Yet, there remain many gaps in our knowledge regarding TDP and related neurodegeneration and cognitive impairment. To advance the field requires better defining the TDP pathology of aging syndrome with currently available tools. The hippocampus is vulnerable in most age-related dementias, but little is known about the specific role for TDP pathology in hippocampal degeneration and memory loss in aging. The goal of this proposal is to elucidate the morphologic and neurobehavioral phenotype of TDP pathology. The hypothesis is that TDP has a unique profile of hippocampal degeneration and associated cognitive and behavioral deficits that can be separated from AD and vascular pathologies. We capitalize on a rich large resource of older persons from well characterized and longitudinally followed older community dwelling subjects enrolled without dementia with high follow-up and autopsy rates. In the first aim we investigate brains to study the association of TDP pathology with neurons, astrocyte and microglial densities in multiple regions of hippocampus; and perform a broader search for HS which is patchy and under- recognized. In the second aim we use ex-vivo MRI imaging to link hippocampal size and shape to TDP after controlling for AD and vascular pathologies. In the third aim we create a hippocampal shape/size imaging score for TDP and translate this score from ex-vivo to in-vivo and pathologically validate the marker in those with in-vivo scans that die and come to autopsy. In the fourth aim we investigate the early neurobehavioral and cognitive characteristics of TDP pathology. Finally, in aim 5a we investigate the mechanism by which TDP is associated with memory decline using the new data on neurons, glia, and HS. In 5b we investigate whether the in-vivo TDP imaging score is associated with memory decline and incident Alzheimer’s type dementia. These studies on TDP pathology in aging will advance the field and have a strong potential to enhance and our understanding and the diagnosis of TDP in the spectrum of Alzheimer’s type clinical syndrome.

项目摘要/摘要 TDP已成为与阿尔茨海默氏症临床有关的重要且常见的与年龄有关的病理 综合征。 TDP病理学有大量的大脑，与 情节记忆障碍。 TDP病理发生在“正常衰老”中，有和没有伴随 阿尔茨海默氏病（AD）病理学，作为主要成分海马硬化症（HS）。临床 与TDP病理学相关的综合征模仿，并使阿尔茨海默氏症的临床综合征恶化。 TDP（与 并且没有HS）通常以AD作为混合病理而发生病理学，并降低 痴呆症（降低弹性）。 TDP也发生在没有AD病理诊断的情况下 与记忆丧失和模仿AD的痴呆症分开相关。新兴数据表明TDP 病理具有很大的公共卫生影响。但是，我们关于TDP和 相关的神经变性和认知障碍。要推进该领域，需要更好地定义TDP 衰老综合症的病理学，并具有当前可用的工具。海马在大多数与年龄有关的大多数 痴呆症，但对TDP病理在海马变性和 衰老的记忆力丧失。该提议的目的是阐明形态学和神经行为 TDP病理的表型。假设是TDP具有海马变性的独特特征 相关的认知和行为定义可以与AD和血管病理学分开。我们 利用来自良好特征和纵向遵循的丰富的老年人资源 社区住宅受试者没有痴呆症，其随访和尸检率很高。在第一个目标 我们研究大脑，研究TDP病理与神经元，星形胶质细胞和小胶质细胞的关联 海马多个区域的密度；并对HS进行更广泛的搜索 认可。在第二个目标中，我们使用Ex-Vivo MRI成像将海马大小和形状连接到TDP之后 控制AD和血管病理。在第三个目标中，我们创建海马形状/尺寸成像 TDP的分数并将此分数从前体内转化为体内，并在病理上验证标记 带有Vivo扫描死亡并进行尸检。在第四个目标中，我们调查了早期的神经行为和 TDP病理学的认知特征。最后，在AIM 5A中，我们研究了TDP的机制 使用神经元，神经胶质和HS的新数据与记忆下降相关。在5B中，我们调查了是否 体内TDP成像评分与记忆下降和Alzheimer型痴呆症的事件有关。这些 关于衰老中TDP病理学的研究将推进该领域，并具有强大的增强潜力 在阿尔茨海默氏症类型临床综合征范围内的TDP的理解和诊断。