CLINICOPATHOLOGICAL STUDIES

临床病理学研究

• 批准号: 7255669
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 15.52万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7255669
• 关键词: Alzheimer' s disease; Lewy body; aging; amyloid proteins; amyloidosis; apolipoprotein E; behavioral /social science research tag; brain disorder diagnosis; brain imaging /visualization /scanning; clinical research; cognition disorders; dementia; diagnosis design /evaluation; enzyme linked immunosorbent assay; hippocampus; human old age (65+); human subject; immunologic assay /test; myelin; neurofilament proteins; neuropathology; paired helical filament; tau proteins; ubiquitin

Previous clinicopathological studies have indicated that some elderly individuals have numerous cerebral amyloid deposits, yet remain cognitively intact, a process we call "pathological aging" (PA). It remains uncertain if PA is pre-clinical Alzheimer's disease (AD), but the proposed studies i n the application will address this issue. In particular, clinicopathologic correlations with increasingly sophisticated neuropsychologic measures, such as those developed in Project 2, will be applied to determine if there are cognitive differences between PA and brains with no amyloid deposition. If PA is pre-clinical AD, it will be important to understand the nature of the amyloid that is deposited and the mechanism of its formation, especially if it is one of the earliest markers of AD. While tau pathology in PA is minimal, it will be important to precisely define the nature of tau pathology in PA as well as in cases with cognitive impairment ranging from mild amnestic deficits (amnestic cognitive impairment - ACI) to frank dementia. In this competing renewal, Specific Aim 1 is focused on characterizing amyloid in PA compared to AD, as well as studying the mechanism of amyloid deposition. Specific aim 2 is focused on the hypothesis that progressive tau pathology underlies cognitive impairment in ACI and AD. Studies in this aim will use quantitative analyses and a panel of tau antibodies, including recently developed antibodies specific to exon 10 splice forms of tau, to study progressive abnormalities in tau. Since most clinicopathologic studies of community residing subjects indicate that mild cognitive impairment and AD is often associated with mixed degenerative and vascular pathology, Specific aim 3 is focused on efforts to better characterize vascular pathology in brains to understand the relative contribution of vascular and degenerative lesions to cognitive impairment in the elderly. It will do so through development of novel quantitative assays of white matter pathology and arteriosclerotic vascular disease. In summary, the clinicopathologic correlations that form the underpinnings of this project focus on quantitative analyses of the three major structural pathologies in the aging brain - amyloid, tau and vascular disease.

先前的临床病理学研究表明，一些老年人存在大量脑淀粉样蛋白沉积，但认知能力保持完整，我们将这一过程称为“病理性衰老”（PA）。 PA 是否是临床前阿尔茨海默病 (AD) 仍不确定，但申请中提出的研究将解决这个问题。特别是，临床病理学与日益复杂的神经心理学测量的相关性，例如在 项目 2 将用于确定 PA 和没有淀粉样蛋白沉积的大脑之间是否存在认知差异。如果 PA 是临床前 AD，那么了解沉积的淀粉样蛋白的性质及其形成机制非常重要，特别是如果它是 AD 最早的标志物之一。虽然 PA 中的 tau 蛋白病理学很少，但准确定义 PA 中 tau 蛋白病理学的性质以及认知障碍（从轻度遗忘性缺陷（遗忘性认知障碍 - ACI）到明显痴呆）的情况非常重要。在这个 竞争性更新，具体目标 1 专注于表征 PA 与 AD 中的淀粉样蛋白，以及研究淀粉样蛋白沉积的机制。具体目标 2 集中于以下假设：进行性 tau 病理学是 ACI 和 AD 认知障碍的基础。该目标的研究将使用定量分析和一组 tau 抗体（包括最近开发的针对 tau 外显子 10 剪接形式的特异性抗体）来研究 tau 的进行性异常。由于大多数社区居住受试者的临床病理学研究表明，轻度认知障碍和 AD 通常与混合的退行性和血管病理学相关，因此具体目标 3 的重点是努力更好地表征大脑中的血管病理学，以了解血管和退行性病变对老年人的认知障碍。它将通过开发白质病理学和动脉硬化性血管疾病的新型定量分析来实现这一目标。总之，构成该项目基础的临床病理相关性侧重于对衰老大脑中三种主要结构病理学——淀粉样蛋白、tau 蛋白和血管疾病的定量分析。