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

项目二摘要/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患者都有高 活体和广泛淀粉样蛋白扫描时PET淀粉样蛋白结合放射性配基如PIB的摄取 死亡时的存款。然而，认知正常的人在淀粉样蛋白PET扫描呈阳性时会出现 悬而未决的难题：他们是否正在走向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 大脑具有特殊的特性，这使得它们不太容易受到A？的神经毒性影响。这个项目将 直接通过定义淀粉样蛋白个体的神经病理表型来解决这个问题 成像阳性和认知正常，并记录与淀粉样蛋白成像阳性者的差异 以及认知功能受损。此外，通过对期间发生的病理变化进行详细分析 在疾病的最早时间点，我们将能够识别导致痴呆症状的变化的演变 并确定有用的替代标记物来指导早期诊断，如新的体内神经成像技术。 我们将检验这些主要假设：1)内嗅皮层的神经元丢失在 在个体出现症状之前的阿尔茨海默病的临床前阶段；2)可溶性寡聚体A？水平将是 受损的病例更严重：3)非淀粉样变性改变，如tau损害，将与神经元密切相关。 淀粉样蛋白成像阳性病例的丢失和4)突触丢失和胶质细胞激活将与临床相关 症状并标志着向症状阶段的过渡；这些变化在有弹性的人中不会那么明显 案子。为了实现这些目标，我们已经与其他四个ADC建立了工作合作 (梅奥、匹兹堡大学、华盛顿大学和哥伦比亚大学)共享临床和神经成像数据 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 成像阳性且认知受损，淀粉样蛋白成像阴性且认知正常。通过识别 在淀粉样蛋白开始堆积之后但症状出现之前的几年内发生的神经生物因素 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 A¿. 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 A¿ 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.