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；

基本信息

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
项目类别：
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

项目摘要

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.

抽象的老年海马硬化（HS）是老年人中一种重要的退行性病理。这是死于痴呆症的人多达三分之一的脑部尸检样本中存在这种物质，并且具有更强的在这个年龄组中，与痴呆症的关联性高于阿尔茨海默病神经病理学（ADNP）。异常- 一些人认为 43 kDa TAR DNA 结合蛋白 (TDP-43) 的错误磷酸化是 HS 的根本原因。 HS 和 TDP-43 蛋白病只能在死后诊断为没有可用的生物标志物。目前，热射病的诊断取决于其存在和消除 ADNP 的格力。这使得研究这些病理及其之间的关系变得不可能独立的危险因素。此外，人们越来越认识到 TDP-43 与 thology 和 HS 有必要在父项目中阐明这种关系。然而，当前仅在父项目中租用用于脑样本病理评估的国家指南建议对大脑进行有限的 TDP-43 病理检查。这可能反过来导致认识 TDP-43 病理学的程度。鉴于年龄最大的老年人成长最快的事实我们人口中痴呆症发病率最高的部分，迫切需要改善该年龄段这些重要的退行性神经病理学的诊断。在此补充中，我们建议改善海马硬化和 TDP-43 神经病理学特征通过提供独立于 ADNP 的更详细的 HS 评估和前检测大脑的额外部分是否存在 TDP-43 病理学。在目标 1 中，我们将检查来自父项目的 450 个尸检大脑的幻灯片，仅根据 HS 相关区域存在不成比例的萎缩。我们假设分配 HS 诊断独立于 ADNP 的疾病将导致 HS 诊断人数显着增加姐姐。在目标 2 中，我们将在 450 例尸检中检查颞叶的额外大脑部分母项目的大脑确定异常 TDP-43 病理学的存在，从而使更多预对 TDP-43 病理学传播的正确认识。我们假设测定颞叶 TDP-43 病理负荷将导致晚期病例数显着增加 TDP-43 病理学。完成拟议的工作将有助于对海马硬化症进行更可靠的识别及其与 TDP-43 病理学的关系。这是朝着更好地理解与痴呆症相关的重要病理学在增长最快的人群中发病率最高痴呆症。