Diagnosis and risk factors of hippocampal sclerosis of aging; a common Alzheimer's mimic in the oldest old

老年性海马硬化的诊断及危险因素；

• 批准号: 10294794
• 负责人: Seyed Ahmad Sajjadi
• 金额: $ 40.78万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294794
• 关键词: Aged, 80 and over; Aging; Alzheimer' s Disease; Area; Atrophic; Autopsy; Biological Markers; Blood Vessels; Brain; Clinical; Cognitive; Dementia; Diagnosis; Diagnostic; Encephalopathies; Gliosis; Goals; Guidelines; Hippocampal Formation; Hippocampus (Brain); Image; Impaired cognition; Laboratories; Lead; Leadership; Life; Measures; Methods; Parents; Pathologic; Pathology; Phosphorylation; Population; Public Health; Recommendation; Research; Risk Factors; Sampling; Serology; Slide; Temporal Lobe; Work; age group; age related; base; biomarker development; hippocampal sclerosis; imaging biomarker; improved; limbic-predominant age-related TDP-43 encephalopathy; neuropathology; parent project; protein TDP-43

Abstract Hippocampal sclerosis of aging (HS) is an important degenerative pathology in the oldest old. It is present in up to a third of brain autopsy samples of those who die with dementia and has a stronger association with dementia than Alzheimer's disease neuropathology (ADNP) in this age group. Abnor- mal phosphorylation of TAR DNA binding protein of 43 kDa (TDP-43) is considered by some to be the underlying reason for HS. HS and TDP-43 proteinopathy can only be diagnosed at post-mortem as there are no available biomarkers. Currently, diagnosis of HS is dependent upon presence and de- gree of ADNP. This makes it impossible to study the relationship between these pathologies and their risk factors independently. Moreover, the increasing recognition of the relation between TDP-43 pa- thology and HS has necessitated elucidation of this relationship in the parent project. However, cur- rent national guidelines used for pathological assessment of brain samples in the parent project, only recommend a limited examination of brain for TDP-43 pathology. This might in turn lead to under- recognition of the extent of TDP-43 pathology. Given the fact that the oldest old are the fastest grow- ing segment of our population with the highest rate of dementia, there is a pressing need to improve the diagnosis of these important degenerative neuropathologies in this age group. In this supplement, we propose improving hippocampal sclerosis and TDP-43 neuropathological char- acterization by providing more detailed assessment of HS that are independent of ADNP and by ex- amining extra sections of the brain for presence of TDP-43 pathology. In Aim 1, we will examine the slides from 450 autopsied brains of the parent project to assign HS diagnosis solely based on the presence of disproportionate atrophy in HS relevant areas. We hypothesize that assigning HS diag- nosis independent of ADNP will lead to a significant increase in the number of those with HS diagno- sis. In Aim 2, We will examine an extra section of the brain from temporal lobe in 450 autopsied brains of the parent project to determine presence of abnormal TDP-43 pathology enabling more pre- cise recognition of TDP-43 pathology spread. We hypothesize determination of temporal lobe TDP-43 pathology load will lead to a significant increase in the number of cases with the most advanced stage of TDP-43 pathology. Completion of the proposed work will lead to a more robust identification of hippocampal sclerosis and its relationship to TDP-43 pathology. This is an important step towards better understanding of an important dementia related pathology in the fastest growing segment of population with highest rates of dementia.

抽象的 衰老的海马硬化症（HS）是最古老的老年病毒性病理学。这是 最多三分之一的脑尸检样本的患者死于痴呆症患者 与痴呆症相比，该年龄段的阿尔茨海默氏病神经病理学（ADNP）。 ab 某些人认为有43 kDa（TDP-43）的TAR DNA结合蛋白的麦磷酸化被某些人视为 HS的根本原因。 HS和TDP-43蛋白质病只能在验尸时诊断为 没有可用的生物标志物。目前，HS的诊断取决于存在和诊断 ADNP的Gree。这使得不可能研究这些病理及其它们的关系 独立风险因素。此外，对TDP-43 PA-之间关系的越来越多的认识 Thology和HS需要在父项目中阐明这种关系。但是， 租金用于对父母项目中大脑样本的病理评估的国家准则，仅 建议对TDP-43病理学的大脑检查有限。这反过来可能导致 识别TDP-43病理的程度。鉴于最古老的是最快的成长 - 我们人口的痴呆率最高的人群，迫切需要改善 这些年龄段的这些重要退化性神经病理学的诊断。 在这种补充剂中，我们提出了改善海马硬化和TDP-43神经病理学char- 通过对独立于ADNP的HS进行更详细的评估，并通过 在存在TDP-43病理学的情况下宽松大脑的额外部分。在AIM 1中，我们将检查 来自父母项目的450个动体大脑的幻灯片，仅根据 HS相关地区的存在不成比例的萎缩。我们假设分配HS Diag- 与ADNP无关的NOSIS将导致HS诊断的人数显着增加 sis。在AIM 2中，我们将检查450台颞叶的额外大脑部分 母体项目的大脑确定存在异常TDP-43病理学的存在，从而使得更多 CISE识别TDP-43病理传播。我们假设确定颞叶TDP-43 病理负荷将导致最先进阶段的病例数量显着增加 TDP-43病理学。 拟议工作的完成将导致海马硬化的更强大的鉴定 及其与TDP-43病理学的关系。这是更好地理解一个的重要一步 重要的痴呆症与痴呆症相关的病理学中，增长最快的人群的比率最高 痴呆症。