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

摘要 老年海马硬化症(HS)是高龄老年人的一种重要退行性病变。它是 存在于高达三分之一的痴呆症死亡患者的脑部尸检样本中，且有更强的 在这个年龄段，与阿尔茨海默病神经病理学(ADNP)相比，痴呆症的相关性更强。艾伯纳- 43 kDa TAR DNA结合蛋白(TDP-43)的MAL磷酸化被一些人认为是 造成HS的根本原因。HS和TDP-43蛋白病只能在尸检时诊断为 没有可用的生物标志物。目前，HS的诊断依赖于HS的存在和解除 ADNP的格里。这使得研究这些病理和它们之间的关系是不可能的 独立的风险因素。此外，人们对TDP-43pa和TDP-43pa之间关系的认识日益加深。 Tology和HS有必要在母项目中阐明这种关系。然而，现在- 仅适用于父项目中用于脑组织样本病理评估的国家指南 建议对TDP-43病理进行有限的脑部检查。这可能会反过来导致- 对TDP-43病理范围的认识。考虑到年龄最大的老年人是成长最快的- 在我们痴呆症发病率最高的人群中，迫切需要改善 这些重要的退行性神经病变在这个年龄段的诊断。 在本补充材料中，我们建议改善海马区硬化和TDP-43神经病理特征。 通过提供独立于ADNP的更详细的HS评估和前 检查大脑的额外部分，以确定是否存在TDP-43病理。在目标1中，我们将研究 从父项目的450个尸检大脑中提取幻灯片，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- 不依赖ADNP的NOIS将导致HS诊断人数的显著增加。 姐姐。在目标2中，我们将检查450例尸检的大脑颞叶的额外部分 大脑的父母项目，以确定是否存在异常的TDP-43病理，使更多的前期 Cise对TDP-43病理传播的认识。我们假设颞叶TDP-43的测定 病理负荷将导致最晚期病例的数量显著增加 TDP-43病理学。 拟议工作的完成将导致对海马体硬化症的更有力的识别 及其与TDP-43病理的关系。这是朝着更好地理解 人口增长最快、发病率最高的人群中与痴呆相关的重要病理 痴呆症。

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.