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

描述（由申请人提供）：在阿尔茨海默病（AD）领域，有多种疾病发生理论。尽管标志性的生理特征- - -淀粉样斑块和tau神经原纤维缠结- - -可以诊断出这种疾病，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。本研究将海马复合体（HC）的高分辨率磁共振成像（MRI）与两种正电子发射断层扫描（PET）技术相结合，研究携带和不携带AD风险基因载脂蛋白E4的受试者的蛋白质沉积、HC神经元损失和皮层变薄之间的关系。研究的第一个PET配体[F18]FDDNP是β -淀粉样斑块和tau神经原纤维缠结沉积的标志物；第二种，[F18]MPPF与HC锥体细胞中特异性发现的血清素1A受体结合，可作为HC神经元损失的测量指标。海马体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第一个显示ad相关变化的大脑区域。这两种PET测量方法将与Bookheimer实验室开发的计算海马展开技术相结合，在严重的认知症状出现之前很久就能识别大脑和HC中的生理AD症状。我们将比较认知正常和轻度记忆受损的老年人的蛋白质沉积、皮层变薄和神经元丢失，这些老年人有和没有AD的遗传风险。这些措施将与神经心理学测试评估的认知功能相关联。这项研究将有助于开发识别阿尔茨海默病最初变化的方法，并将识别与记忆衰退最相关的阿尔茨海默病的病理特征。这一知识对阿尔茨海默病的早期识别和确定早期干预的最佳目标具有重要意义。

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.