IMPLICATIONS OF AMYLOID DEPOSITION IN CLINICALLY NORMAL OLDER INDIVIDUALS

拟议研究的总体目标是调查临床正常的老年人是否有 纤维状淀粉样蛋白沉积的证据是在阿尔茨海默病的前驱期。我们将研究 100名临床正常个体（CDR 0; MMSE 27-30;年龄和教育方面的表现<1.5 SD） 匹配的神经心理学测试标准）与PIB PET淀粉样蛋白成像，以实现三个特定目标：1） 探讨正常人高淀粉样蛋白沉积的相关因素，包括年龄、认知功能、 AD的遗传危险因素; 2）研究正常人是否存在高淀粉样蛋白血症， 负荷显示功能和结构成像测量异常，符合 在前驱AD中观察到的改变;以及3）为了确定具有高淀粉样蛋白沉积的正常人是否更多地 可能在情景记忆的敏感指标上表现出临床下降，并进展到 轻度认知障碍（MCI）。我们的初步数据，以及其他团体的报告，表明， 相当大比例的临床正常个体在PIB PET上具有淀粉样蛋白沉积的证据 成像，其模式类似于临床AD中观察到的模式。我们的初步数据表明这些正常人 高淀粉样蛋白沉积显示在特定的脑组织中的功能和结构改变 区域，类似于MCI和AD中通常报告的图像异常模式。我们假设 较高水平的PIB保留将与功能性MRI和FDG的较大功能异常相关， PET成像，以及体积MRI上内侧颞叶和顶叶皮质的更大萎缩。 此外，我们假设，正常人高淀粉样蛋白负荷将表现出损害的挑战， 情景记忆测试，并将证明MCI临床下降的可能性更高， 最后是临床AD。这个项目将大量利用MADRC的资源，特别是 临床核心、神经影像子核心和数据/统计核心的纵向队列，以及 与项目2和3中淀粉样蛋白沉积的研究密切相关。 相关性（参见说明）： AD的长的症状前阶段为有效的潜在干预提供了关键机会。 治疗然而，开发生物学和成像标记物来追踪疾病是至关重要的 症状前阶段的进展并预测临床症状的发作。本项目将提供 关于淀粉样蛋白沉积与脑功能障碍和临床衰退关系的基本信息。

The overall goal of the proposed research is to investigate whether clinically normal older individuals with evidence of fibrillar amyloid deposition are in the prodromal phases of Alzheimer's disease. We will study 100 clinically normal individuals (CDR 0; MMSE 27-30; performance within <1.5 SD on age and education matched neuropsychological test norms) with PIB PET amyloid imaging to accomplish three specific aims: 1) To investigate the factors associated with high amyloid deposition in normals, including age, cognitive reserve, family history and genetic risk-factors for AD; 2) To investigate whether normals with high amyloid burden demonstrate abnormalities on functional and structural imaging measures, consistent with the alterations seen in prodromal AD; and 3) To determine if normals with high amyloid deposition are more likely to demonstrate clinical decline on sensitive measures of episodic memory and progress to a stage of mild cognitive impairment (MCI). Our preliminary data, as well as reports from other groups, suggest that a substantial proportion of clinically normal individuals have evidence of amyloid deposition on PIB PET imaging, in a pattern similar to that observed in clinical AD. Our preliminary data suggest that these normals with high amyloid deposition demonstrate functional and structural alterations in a specific set of brain regions, similar to the pattern of image abnormality commonly reported in MCI and AD. We hypothesize that higher levels of PIB retention will correlate with greater functional abnormality on functional MRI and FDG- PET imaging, as well as greater atrophy in medial temporal lobe and parietal cortices on volumetric MRI. Furthermore, we hypothesize that normals with high amyloid burden will manifest impairment on challenging episodic memory tests, and will demonstrate a higher likelihood of clinical decline towards MCI and ultimately clinical AD. This project will draw heavily on the resources of the MADRC, in particular, the Longitudinal Cohort of the Clinical Core, the Neuroimaging SubCore, and the Data/Statistics Core, as well as interface closely with the investigation of amyloid deposition in Projects 2 and 3. RELEVANCE (See instructions): The long presymptomatic phase of AD provides a critical opportunity for potential intervention with effective therapies. It is essential, however, to develop biological and imaging markers that will track disease progression in the presymptomatic phases and predict onset of clinical symptoms. This project will provide fundamental information on the relationship of amyloid deposition to brain dysfunction and clinical decline.