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: 9899911
• 负责人: Seyed Ahmad Sajjadi
• 金额: $ 71.48万
• 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/9899911
• 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; Serological; 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; 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 衰老（HS）的海马硬化症（HS）中有多达三分之一的脑尸检样品的年龄超过90岁 死于痴呆症的老人。与阿尔茨海默氏病病理学（AD）相比，HS病理学更强大 最古老的痴呆症的预测因子。尽管它很重要，但由于缺乏，HS仍然是事后诊断 可以预测生活中病理的特定生物标志物。大多数携带HS病理学的患者是 被误诊为阿尔茨海默氏病。考虑到最古老的老年人的痴呆症患病率很高 增长最快的人群，迫切需要诊断这一重要原因 在这个年龄段。除了精确诊断在生活中研究HS的重要性外，我们最近还 确定了自身免疫，甲状腺疾病和甲状腺的HS与临床史之间的关联 抗体。这意味着如果早日诊断出HS可能是可修改的条件。 90多个研究，之一 最大的痴呆症研究及其在最古老的老旧研究中，为研究HS提供了理想的平台 与90岁的年龄段相比，该病情在年龄较大的年龄较大两倍。 在AIM 1中，我们将测试与AD相比的假设，HS患者具有显着的发作性损害 在痴呆症和纵向的轻度阶段的记忆。我们还将研究这些纵向过程 两个条件测试了HS患者的认知能力下降率较慢的假设。在AIM 2中，使用 T1和T2 MRI序列，我们将检验以下假设： 海马和海马T2松弛增加可以利用生命中的AD诊断HS。 我们还将检验以下假设：最古老的旧记忆障碍与CA1显着相关 区域萎缩和海马T2信号变化。在AIM 3中，我们将评估HS与 自身免疫和甲状腺功能的血清学标记。通过对这些标记的年度测量，我们 将检验以下假设，即自身免疫和甲状腺疾病的血清学标志物水平异常 在患有HS病理学的患者中，与HS和痴呆症有关，提供了假定的机械联系。 这项研究完成后，我们将确定一组神经心理学，成像和血清学标记物 能够诊断生活中这种重要且正在研究的痴呆症原因。而且，阐明 HS与自身免疫之间的关系对于预防疾病和未来的药物发现很重要。 鉴于我们不受限制地访问了最大的老年人群之一，我们很好 准备利用神经心理学数据并获取研究的成像和血清学数据 在我们的大部分人群中，常见但知之甚少的痴呆原因。