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

摘要 老年性海马硬化症（HS）存在于90岁以上的大脑尸检样本中的三分之一， 死于痴呆症的奥尔兹与阿尔茨海默病病理学（AD）相比，HS病理学更强， 老年痴呆症的预测因子。尽管它的重要性，HS仍然是一个死后诊断，由于缺乏 特定的生物标志物，可以预测生命中的病理。大多数患有HS病理的患者 被误诊为老年痴呆症考虑到老年痴呆症的高患病率， 我们人口中增长最快的部分，迫切需要诊断痴呆症的重要原因 在这个年龄组。除了在生活中研究HS的准确诊断的重要性外，我们最近 确定了HS与自身免疫、甲状腺疾病和甲状腺疾病的临床病史之间的相关性， 抗体的这意味着HS可能是一种可改变的条件，如果它被早期诊断。90+研究， 老年痴呆症及其危险因素的最大研究，为研究HS提供了完美的平台， 与90岁以下年龄组相比，这种情况在老年人中的常见程度是老年人的两倍。 在目标1中，我们将检验这样一个假设，即与AD相比，HS患者的发作性损害显著。 在轻度痴呆阶段和纵向上的记忆。我们还将研究这些的纵向过程 这两个条件检验了HS患者认知能力下降速度较慢的假设。在目标2中，使用 T1和T2 MRI序列，我们将测试的假设，不成比例萎缩的CA1区的 海马和海马T2弛豫增加可以用来诊断生活中AD引起的HS。 我们还将检验这一假设，即年龄最大的老年人的记忆障碍与CA1显著相关。 海马T2信号改变。在目标3中，我们将评估HS与 自身免疫和甲状腺功能的血清学标志物。通过每年测量这些指标，我们 将检验以下假设：自身免疫和甲状腺疾病的血清学标志物水平异常， 与HS相关，并在HS病理学提供了假定的机制联系的那些痴呆症。 在这项研究完成后，我们将确定一组神经心理学，影像学和血清学标志物， 使诊断这一重要的和未充分研究的原因痴呆症在生活中。此外，阐明 HS和自身免疫之间的关系对于疾病预防和未来的药物发现是重要的。 鉴于我们不受限制地接触到最大和最具特点的老年人群体之一，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， 在我们人口的这一大部分中，痴呆症是一种常见但知之甚少的原因。

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.