Brain Amyloid Accrual in Non Demented People: Preclinical AD or Brain Resilience

项目二概要/摘要 脑淀粉样变性是阿尔茨海默病（AD）的一个恒定特征;几乎所有AD患者都具有高的脑淀粉样变性。 在生命期间扫描时PET淀粉样蛋白结合放射性配体（如PiB）的摄取和广泛的淀粉样蛋白 死亡时的存款然而，认知正常的人，淀粉样蛋白阳性PET扫描， 未解决的难题：他们是否在通往AD的道路上，如果有足够的时间，他们是否会患上痴呆症，或者他们是否会患上痴呆症。 大脑具有特殊的功能，使其不易受到A12的神经毒性作用。该项目将 通过定义淀粉样蛋白个体的神经病理学表型， 成像阳性且认知正常，并记录与淀粉样蛋白成像阳性者的差异 认知能力受损此外，通过对在治疗期间发生的病理变化进行详细分析， 在疾病的最早期，我们将能够确定导致痴呆症状的变化的演变 并鉴定有用的替代标记物以指导早期诊断，例如新的体内神经成像技术。 我们将测试这些主要假设：1）内嗅皮层的神经元损失在大脑皮层发育过程中逐渐形成。 在个体出现症状之前的AD的临床前阶段; 2）可溶性寡聚腺苷酸水平将被检测到。 在受损病例中更大：3）非淀粉样蛋白变化，如tau病变，将与神经元损伤密切相关。 淀粉样蛋白成像阳性病例中的丢失和4）突触丢失和胶质细胞活化将与临床相关 症状和标志着过渡到症状阶段;这些变化将不那么突出的弹性 例为了实现这些目标，我们与其他四个ADC建立了工作合作关系 (Mayo、匹兹堡大学、华盛顿大学和哥伦比亚大学）共享临床和神经影像学数据 以及来自三组受试者的脑组织：淀粉样蛋白成像阳性和认知正常，淀粉样蛋白 成像阳性和认知受损，淀粉样蛋白成像阴性和认知正常。通过识别 在淀粉样蛋白开始积累后但在症状出现前的几年中发生的神经生物学因素 显然，我们将为指导下一代神经成像和其他诊断测试奠定基础 为未来有效的治疗干预确定合理的目标。

PROJECT TWO SUMMARY/ABSTRACT Brain amyloidosis is a constant feature of Alzheimer's disease (AD); almost all patients with AD have high uptake of PET amyloid-binding radioligands such as PiB when scanned during life and extensive amyloid deposits at death. Cognitively normal individuals who have amyloid positive PET scans however present an unresolved conundrum: are they on the road to AD and will develop dementia given enough time, or do their brains have specific features that render them less vulnerable to the neurotoxic effects of Aß. This project will directly address this question by defining the neuropathological phenotype of individuals who are amyloid imaging positive and cognitively normal and document differences with those who are amyloid imaging positive and cognitively impaired. Further, by conducting detailed analyses of the pathological changes that occur during the earliest point in disease, we will be able to identify the evolution of changes that lead to dementia symptoms and identify useful surrogate markers to guide early diagnosis such as novel in vivo neuroimaging techniques. We will test these major hypotheses: 1) neuronal loss in the entorhinal cortex builds gradually during the preclinical phase of AD before an individual becomes symptomatic; 2) soluble oligomeric Aß levels will be greater in the impaired cases: 3) non-amyloid changes, such as tau lesions, will correlate closely with neuronal loss in amyloid imaging positive cases and 4) synaptic loss and glia activation will correlate with clinical symptoms and mark the transition to symptomatic stages; these changes will be less prominent in the resilient cases. In order to accomplish these goals, we have established working collaborations with four other ADCs (Mayo, University of Pittsburgh, Washington University and Columbia) to share clinical and neuroimaging data as well as brain tissue from three groups of subjects: Amyloid imaging positive and cognitively normal, amyloid imaging positive and cognitively impaired, and amyloid imaging negative and cognitively normal. By identifying neurobiologic factors that occur during the years after amyloid begins to accumulate but before symptoms manifest, we will set the stage for guiding the next generation of neuroimaging and other diagnostic tests as well as define rational targets for future effective therapeutic interventions.