PET and MRI Neuronal Loss and Amyloid and Tau Deposition in Alzheimer Disease

阿尔茨海默病中的 PET 和 MRI 神经元丢失以及淀粉样蛋白和 Tau 蛋白沉积

• 批准号: 8304216
• 负责人: Laurel Martin-Harris
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2013-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304216
• 关键词: Address; Adult; Affect; Aging; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Animals; Anterior; Apolipoprotein E; Area; Binding; Brain; Brain region; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cognitive; Complex; Cost of Illness; Dementia; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Early identification; Early treatment; Elderly; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Risk; Goals; Health Care Costs; Hippocampus (Brain); Human; Imagery; Impaired cognition; Incidence; Individual; Investigation; Knowledge; Label; Laboratories; Learning; Ligand Binding; Ligands; Longevity; Magnetic Resonance Imaging; Measurement; Measures; Medicare; Memory; Memory Loss; Methods; Neocortex; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Neuropsychological Tests; Patients; Pattern; Performance; Physiological; Population; Positron-Emission Tomography; Proteins; Pyramidal Cells; Recovery; Relative (related person); Research; Resolution; Risk; Senile Plaques; Serotonin; Signal Transduction; Site; Staging; Symptoms; Techniques; Thick; Time; Work; apolipoprotein E-4; cognitive function; disorder prevention; entorhinal cortex; genetic risk factor; healthy aging; hippocampal pyramidal neuron; improved; in vivo; mild neurocognitive impairment; neuron loss; pre-clinical; public health relevance; receptor; receptor density; tau Proteins; tau aggregation; theories; tool

DESCRIPTION (provided by applicant): Within the field of Alzheimer's Disease (AD) there are multiple theories of disease genesis. Although the hallmark physiological features- beta-amyloid plaques and tau neurofibrillary tangles- are diagnostic for the disorder, it is unknown whether the deposition of these proteins is the cause of neuronal death and cognitive symptoms. This proposal combines high resolution magnetic resonance imaging (MRI) of the hippocampal complex (HC) with two positron emission tomography (PET) techniques to investigate the relationship between protein deposition, HC neuronal loss and cortical thinning in subjects with and without the AD risk gene apolipoprotein E4. The first PET ligand studied, [F18]FDDNP, is a marker for beta-amyloid plaque and tau neurofibrillary tangle deposition; the second, [F18]MPPF binds to the serotionin 1A receptor, found specifically in pyramidal cells of the HC, and can be used as a measure of HC neuronal loss. The hippocampal complex is the primary site for formation of new memories, and is probably the first brain region showing AD-related changes in the early, preclinical stage. These two PET measures will be combined, in conjuction with a computational hippocampal unfolding technique developed by the Bookheimer laboratory, to identify physiological AD symptoms in the brain and HC long before serious cognitive symptoms have developed. We will compare protein deposition, cortical thining and neuronal loss in cognitively normal and mildly memory impaired older adults with and without a genetic risk for developing AD. These measures will be correlated with cognitive function assesed by neuropsychological testing. This research will help develop methods for identifying the first changes in AD, and will identify pathological features of AD that are most related to memory decline. This knowledge has strong implications for both early identification of AD and for identifying the optimal targets of early intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common form of dementia and, according to the Center for Disease Control and Prevention, affects as many as five million Americans, surpassing diabetes to become the 6th leading cause of death among American adults; incidence increases with lifespan and the healthcare cost of this illness becomes astronomical, with AD affecting less than 13% of the Medicare population but responsible for 34% of Medicare spending (estimated to be $91 billion in 2005). Furthermore, by the time the disease symptoms are severe neuronal loss is extensive making recovery difficult at advanced stages. The goal of this research is to develop a better understanding of AD by combining positron emission tomography and magnetic resonance imaging to study the relationship between hallmark protein deposition and neuronal loss in subjects at risk for Alzheimer's disease before cognitive decline is apparent. This work will aid the development of sensitive and reliable methods of early AD detection that can be implemented long before symptoms emerge to drastically improve diagnosis and treatment. At the same time this investigation will contribute to our knowledge of the effects of healthy aging on human learning and memory.

描述（由申请人提供）：在阿尔茨海默病（AD）领域内，存在多种疾病发生的理论。虽然标志性的生理特征-β-淀粉样蛋白斑块和tau神经元缠结-是该疾病的诊断，但尚不清楚这些蛋白质的沉积是否是神经元死亡和认知症状的原因。该建议结合了高分辨率磁共振成像（MRI）的海马复合体（HC）与两个正电子发射断层扫描（PET）技术，以研究蛋白质沉积，HC神经元损失和皮质变薄的受试者与AD风险基因载脂蛋白E4之间的关系。研究的第一种PET配体[F18]FDDNP是β-淀粉样蛋白斑块和tau神经元缠结沉积的标志物;第二种[F18]MPPF与血清素1A受体结合，特异性地发现于HC的锥体细胞中，并且可以用作HC神经元损失的测量。海马复合体是形成新记忆的主要部位，并且可能是在早期临床前阶段显示AD相关变化的第一个大脑区域。这两种PET测量将结合Bookheimer实验室开发的计算海马展开技术，以在严重的认知症状出现之前很久就确定大脑和HC中的生理AD症状。我们将比较蛋白质沉积，皮质变薄和神经元丢失在认知正常和轻度记忆受损的老年人和没有遗传风险的发展AD。这些措施将与通过神经心理学测试评估的认知功能相关。这项研究将有助于开发识别AD最初变化的方法，并将识别与记忆衰退最相关的AD病理特征。这些知识对早期识别AD和确定早期干预的最佳目标具有重要意义。 公共卫生相关性：阿尔茨海默病（AD）是最常见的痴呆形式，根据疾病控制和预防中心的数据，影响多达500万美国人，超过糖尿病成为美国成年人的第六大死亡原因;发病率随着寿命的增加而增加，并且这种疾病的医疗保健费用变得天文数字，AD影响不到13%的Medicare人群，但占Medicare支出的34%（2005年估计为910亿美元）。此外，当疾病症状严重时，神经元损失是广泛的，使得在晚期阶段难以恢复。本研究的目的是通过结合正电子发射断层扫描和磁共振成像来研究在认知能力下降明显之前有阿尔茨海默病风险的受试者中标志性蛋白沉积和神经元损失之间的关系，从而更好地了解AD。这项工作将有助于开发早期AD检测的敏感和可靠方法，这些方法可以在症状出现之前很久就实施，从而大大改善诊断和治疗。同时，这项研究将有助于我们了解健康老龄化对人类学习和记忆的影响。