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

摘要 在90岁以上的大脑尸检样本中，多达三分之一的人患有海马体老化硬化症。 死于痴呆症的老人。与阿尔茨海默病病理学(AD)相比，HS病理学的作用要强得多 高龄老人痴呆症的预测指标。尽管它很重要，但由于缺乏，HS仍然是一个尸检诊断 可以预测生命中的病理的特定生物标记物。大多数患有HS病理的患者都是 被误诊为阿尔茨海默病。鉴于痴呆症在年龄最大的老年人中的高发病率，谁是 在我们人口增长最快的部分，迫切需要诊断这一导致痴呆症的重要原因 在这个年龄段。除了准确的诊断对于在生活中学习HS的重要性外，我们最近还 确定HS与自身免疫、甲状腺疾病和甲状腺的临床病史之间的关联 抗体。这意味着如果及早诊断，HS可能是一种可修改的疾病。90年代的研究，其中之一 对高龄老人痴呆症及其危险因素的最大规模研究为研究HS AS提供了完美的平台 与90岁以下的年轻人相比，这种情况在老年人中的常见程度是后者的两倍。 在目标1中，我们将检验假设，与AD相比，HS患者具有显著的发作性损害 在轻度痴呆症阶段和纵向记忆。我们还将研究这些问题的纵向过程 两种情况验证了HS患者认知衰退速度较慢的假设。在目标2中，使用 T1和T2磁共振序列，我们将检验假设CA1区不成比例的萎缩 海马区和增加的海马区T2松弛可以用来诊断生活中AD的HS。 我们还将测试这一假设，即年龄最大的老年人的记忆障碍与CA1显著相关 脑区萎缩，海马区T2信号改变。在目标3中，我们会评估房协与 自身免疫和甲状腺功能的血清学标志物。通过对这些标记的年度测量，我们 将检验一种假设，即自身免疫和甲状腺疾病的血清标志物异常水平 在有HS病理的患者中，与HS相关，并先于痴呆，这提供了一种假定的机制联系。 在这项研究完成后，我们将确定一组神经心理学、影像和血清学标记物 能够诊断出这一重要且未被充分研究的痴呆病因。此外，澄清 HS与自身免疫的关系对于疾病的预防和未来的药物开发具有重要意义。 考虑到我们不受限制地接触到最大和最具特征的最年长的老年人之一，我们很好 准备利用神经心理学数据，并获得研究这一问题所需的成像和血清学数据 在我们人口中的这一大部分人中，痴呆的常见但鲜为人知的原因。

Abstract Hippocampal sclerosis of aging (HS) is present in up to a third of brain autopsy samples of older than 90-year- olds who die with dementia. Compared to Alzheimer's disease pathology (AD), HS pathology is a much stronger predictor of dementia in the oldest old. Despite its importance, HS remains a post-mortem diagnosis due to lack of specific biomarkers that can predict the pathology during life. Most patients harboring HS pathology are misdiagnosed as Alzheimer's disease. Given the high prevalence of dementia in the oldest old, who are the fastest growing segment of our population, there is an urgent need to diagnose this important cause of dementia in this age group. In addition to the importance of accurate diagnosis for studying HS during life, we have recently identified an association between HS and clinical history of autoimmunity, thyroid disease, and thyroid antibodies. This implies HS might be a modifiable condition should it be diagnosed early. The 90+ study, one of the largest studies of dementia and its risk factors in the oldest old, provides the perfect platform to study HS as the condition becomes twice as common in the older compared to younger than 90-year-old age group. In aim 1, we will test the hypothesis that compared to AD, HS sufferers have a significant impairment of episodic memory both at mild stages of dementia and longitudinally. We will also examine the longitudinal course of these two conditions testing the hypothesis that HS sufferers have a slower rate of cognitive decline. In aim 2, using T1 and T2 MRI sequences, we will test the hypothesis that disproportionate atrophy of CA1 region of hippocampus and increased hippocampal T2 relaxation can be leveraged to diagnose HS from AD during life. We will also test the hypothesis that memory impairment in the oldest old is significantly associated with CA1 region atrophy and hippocampal T2 signal change. In aim 3, we will assess the relation between HS and the serological markers of autoimmunity and thyroid function. Through annual measurement of these markers, we will test the hypothesis that abnormal levels of serological markers of autoimmunity and thyroid disease are associated with HS and precede dementia in those with HS pathology providing a putative mechanistic link. At completion of this study, we will identify a set of neuropsychological, imaging, and serological markers that enable the diagnosis of this important and understudied cause of dementia during life. Moreover, elucidation of the relationship between HS and autoimmunity is important for disease prevention and future drug discovery. Given our unrestricted access to one of the largest and best characterized cohorts of the oldest old, we are well poised to utilize the neuropsychological data and acquire the imaging and serological data needed to study this common but poorly understood cause of dementia in this large segment of our population.