PET and MRI Investigation of Neuronal Loss and Amyloid and Tau Deposition in Alzh

描述(由申请者提供)：在阿尔茨海默病(AD)领域，关于疾病发生的理论有多种。尽管标志性的生理特征-β-淀粉样斑块和tau神经纤维缠结-是这种疾病的诊断依据，但这些蛋白质的沉积是否是神经元死亡和认知症状的原因尚不清楚。这项建议结合高分辨率核磁共振成像(MRI)和两种正电子发射断层扫描(PET)技术，研究AD风险基因载脂蛋白E4携带者和不携带者的蛋白质沉积、HC神经元丢失和皮质变薄之间的关系。第一个被研究的PET配体，[F18]FDDNP，是β-淀粉样斑块和tau神经纤维缠结沉积的标志；第二个，[F18]MPPF与血清素1A受体结合，该受体专门在HC的锥体细胞中发现，并可用作HC神经元丢失的衡量标准。海马体是形成新记忆的主要部位，也可能是早期临床前阶段表现出AD相关变化的第一个脑区。这两项PET测量将与布克海默实验室开发的计算海马区展开技术相结合，在严重认知症状出现之前很久就识别大脑和HC中的生理性AD症状。我们将比较认知正常和轻度记忆受损的老年人中的蛋白质沉积、皮质变薄和神经元丢失，其中有和没有发生阿尔茨海默病的遗传风险。这些测量将与神经心理测试评估的认知功能相关。这项研究将有助于开发识别AD的最初变化的方法，并将识别与记忆衰退最相关的AD的病理特征。这一知识对AD的早期识别和确定早期干预的最佳靶点都有很大的意义。 公共卫生相关性：阿尔茨海默病(AD)是最常见的痴呆症形式，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；发病率随着寿命的延长而增加，这种疾病的医疗成本成为天文数字，AD影响到不到13%的联邦医疗保险人口，但占医疗保险支出的34%(2005年估计为910亿美元)。此外，当疾病症状严重时，神经元广泛丢失，使晚期恢复困难。这项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阿尔茨海默病高危人群在认知能力下降明显之前标志蛋白沉积和神经元丢失之间的关系，从而更好地了解阿尔茨海默病。这项工作将有助于开发敏感和可靠的早期阿尔茨海默病检测方法，这些方法可以在症状出现之前很久就实施，以显著改善诊断和治疗。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。

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.