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: 10092061
• 负责人: Seyed Ahmad Sajjadi
• 金额: $ 71.35万
• 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/10092061
• 关键词: Aged, 80 and over; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Antibodies; Atrophic; Autoantibodies; Autoimmunity; Autopsy; Biological Markers; Blood; Brain; Clinical; Clinical Markers; Cognitive; Data; Dementia; Diagnosis; Differentiation Antigens; Disease Marker; Early Diagnosis; Early identification; Funding; Future; Gliosis; Goals; Health Priorities; High Prevalence; Hippocampus (Brain); Image; Impaired cognition; Impairment; Kava; Life; Link; Magnetic Resonance Imaging; Measurement; Measures; Memory; Memory Loss; Memory impairment; Neuropsychology; Participant; Pathology; Patients; Pattern; Performance; Population; Positron-Emission Tomography; Public Health; Recording of previous events; Relaxation; Research; Resolution; Rheumatoid Arthritis; Risk Factors; Sampling; Serology; Serum; Signal Transduction; Syndrome; Testing; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; United States National Institutes of Health; Work; accurate diagnosis; age group; aged; clinical predictors; cohort; disease diagnosis; disorder prevention; drug discovery; episodic memory impairment; hippocampal sclerosis; human old age (65+); imaging biomarker; indexing; longitudinal course; neuron loss; relating to nervous system; serological marker; sex; specific biomarkers; tau Proteins

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.

抽象的 90 岁以上老人的脑部尸检样本中，多达三分之一存在海马衰老硬化症 (HS)。 死于痴呆症的老人。与阿尔茨海默氏病病理学（AD）相比，HS病理学更强 老年痴呆症的预测因子。尽管热射病很重要，但由于缺乏 可以预测生命期间病理的特定生物标志物。大多数患有 HS 病理的患者是 被误诊为阿尔茨海默病。鉴于老年痴呆症的患病率很高， 我们人口增长最快的部分，迫切需要诊断痴呆症的这一重要原因 在这个年龄段。除了准确诊断对于研究生命期间 HS 的重要性之外，我们最近还发现 确定了 HS 与自身免疫、甲状腺疾病和甲状腺临床病史之间的关联 抗体。这意味着如果及早诊断，热射病可能是一种可以改变的疾病。 90+ 研究之一 针对老年人的痴呆症及其危险因素的最大规模研究，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发病率是年轻人的两倍。 在目标 1 中，我们将检验以下假设：与 AD 相比，热射病患者的发作性认知障碍显着受损。 痴呆轻度阶段和纵向记忆。我们还将研究这些的纵向过程 两个条件检验了热射病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，我们将检验 CA1 区域不成比例萎缩的假设 海马体和增加的海马体 T2 松弛可用于诊断生活中 AD 引起的 HS。 我们还将检验以下假设：最年长老人的记忆障碍与 CA1 显着相关 区域萎缩和海马 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。通过对这些标记的年度测量，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，并且在患有 HS 病理学的患者中先于痴呆，提供了假定的机制联系。 这项研究完成后，我们将确定一组神经心理学、影像学和血清学标记物， 能够诊断一生中痴呆症的这一重要且尚未得到充分研究的原因。此外，阐明 HS和自身免疫之间的关系对于疾病预防和未来药物发现很重要。 鉴于我们可以不受限制地接触最大、特征最鲜明的老年人群体之一，我们很好 准备利用神经心理学数据并获取研究此问题所需的成像和血清学数据 在我们这一大部分人口中，痴呆症是常见但知之甚少的原因。