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: 9974875
• 负责人: JULIE A. SCHNEIDER
• 金额: $ 133.26万
• 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/9974875
• 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; Structure; 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.

项目概要/摘要 TDP 已成为与阿尔茨海默病临床相关的重要且常见的年龄相关病理学 综合症。 TDP 病理学存在于大量老年大脑中，并且与以下因素密切且独立相关： 情景记忆障碍。 TDP 病理发生在“正常衰老”中，无论是否伴随 阿尔茨海默病 (AD) 病理学，以及作为主要组成部分的海马硬化症 (HS)。临床上 与 TDP 病理学相关的综合征类似于阿尔茨海默病的临床综合征，并使其恶化。 TDP（与 且没有 HS）病理学通常与 AD 一起作为混合病理学发生，并降低了 AD 的阈值 痴呆（降低复原力）。 TDP 也会在没有 AD 病理诊断的情况下发生，其中 分别与记忆丧失和类似 AD 的痴呆症相关。新数据表明 TDP 病理学对公共卫生有很大影响。然而，我们对 TDP 和 TDP 的认识仍然存在许多差距。 相关的神经退行性变和认知障碍。要推进该领域的发展，需要更好地定义 TDP 使用当前可用的工具对衰老综合征进行病理学研究。海马体在大多数与年龄相关的情况下都很脆弱 痴呆症，但人们对 TDP 病理学在海马变性和痴呆中的具体作用知之甚少。 衰老时记忆力减退。该提案的目标是阐明形态学和神经行为 TDP病理表型。假设 TDP 具有独特的海马变性特征 以及相关的认知和行为缺陷，这些缺陷可以与 AD 和血管病理分开。我们 利用大量丰富的老年人资源，这些资源来自具有明确特征和纵向跟踪的老年人 入组的社区居住受试者没有患有痴呆症，随访率和尸检率很高。在第一个目标中 我们研究大脑以研究 TDP 病理学与神经元、星形胶质细胞和小胶质细胞的关联 海马体多个区域的密度；并对 HS 进行更广泛的搜索，该搜索是不完整且不足的 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，并在病理上验证这些标记 体内扫描会死亡并进行尸检。在第四个目标中，我们研究早期神经行为和 TDP病理学的认知特征。最后，在目标 5a 中，我们研究了 TDP 的机制 使用有关神经元、神经胶质细胞和 HS 的新数据，发现与记忆衰退有关。在 5b 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氏型痴呆有关。这些 衰老中 TDP 病理学的研究将推动该领域的发展，并具有强大的潜力，可以增强我们的研究能力。 阿尔茨海默病型临床综合征谱系中 TDP 的理解和诊断。