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.

项目总结/摘要 TDP已经成为与阿尔茨海默病临床相关的重要和常见的年龄相关病理学， 综合征TDP病理学在大量老年人大脑中发现，并且与以下因素强烈且独立相关： 情景记忆障碍TDP病理发生在“正常老化”中，伴随或不伴随 阿尔茨海默病（AD）病理学，并作为主要成分海马硬化（HS）。临床 与TDP病理学相关的综合征模拟和模仿阿尔茨海默氏临床综合征。TDP（含 和没有HS）病理学通常与AD一起作为混合病理学发生，并且降低了 痴呆症（降低恢复力）。TDP也在没有AD的病理诊断的情况下发生，并且其中 分别与记忆丧失和类似AD的痴呆症有关。数据显示，TDP 病理学对公共卫生有很大的影响。然而，我们对TDP的了解仍然存在许多差距， 相关的神经变性和认知障碍。为了推进该领域的发展，需要更好地定义TDP 衰老综合征的病理学与目前可用的工具。海马体在大多数与年龄有关的 痴呆，但很少有人知道TDP病理学在海马变性和 记忆力衰退这项建议的目的是阐明形态学和神经行为 TDP病理表型。假设TDP具有海马变性的独特特征 以及相关的认知和行为缺陷，这些缺陷可以与AD和血管病变分开。我们 利用大量丰富的老年人资源， 社区居住的受试者没有痴呆症，随访和尸检率高。在第一个目标中 我们研究了大脑，以研究TDP病理学与神经元、星形胶质细胞和小胶质细胞的关系， 海马体多个区域的密度;并对HS进行更广泛的搜索，HS是片状的， 认可.在第二个目标中，我们使用离体MRI成像将海马大小和形状与TDP联系起来， 控制AD和血管病变。在第三个目标中，我们创建海马形状/大小成像， TDP评分，并将该评分从离体转化为体内，并在病理学上验证那些 通过体内扫描死亡后进行尸检。在第四个目标中，我们研究了早期神经行为和 TDP病理的认知特征。最后，在目标5a中，我们研究了TDP是 使用神经元、神经胶质和HS的新数据，在5 B中，我们调查是否 体内TDP成像评分与记忆力下降和阿尔茨海默型痴呆相关。这些 对衰老中TDP病理学的研究将推动这一领域的发展，并有很大的潜力来加强我们的研究。 对TDP在阿尔茨海默病型临床综合征谱中的认识和诊断。