CLINICO-PATHOLOGICAL STUDIES OF AGING AND DEMENTIA

衰老和痴呆的临床病理学研究

• 批准号: 6097947
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 27.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6097947
• 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; postmortem; tau proteins; ubiquitin

Some cognitively intact elderly people have numerous cerebral amyloid deposits, a potentially benign form of senile cerebral amyloidosis referred to as "pathological aging"(PA). Other subjects with PA have cognitive impairment. The goal of this project is to determine the substrates of cognitive impairment in PA and to determine whether or not PA is preclinical AD. Clinicopathological analyses are used to determine if cognitive impairment correlates better with cytoskeletal and synaptic pathology than cerebral amyloid deposition, which is the hallmark of PA. Given that amyloid in PAD differs in several ways from that in AD, measures of heterogeneity of amyloid are included in quantitative assessments. Standardized histopathological, biochemical and morphometric measures are correlated with cross-sectional and longitudinal clinical measures. In particular, paired helical filament-tau (PF-tau), synaptic proteins and specific amyloid peptides are measured with ELISA. Amyloid and PHF-tau "burden" are also measured with the image analysis of tissue sections. Severely impaired subjects from EAS are supplemented with brain bank cases from Mayo Clinic Jacksonville to show that disease progression correlates with progressive PHF-tau accumulation and synapse loss, rather than amyloid deposition. All correlations are made with respect to apolipoprotein-A genotype. Similar assays as those used for "pure" AD and PA cases are performed on brains with "mixed" pathology, including cases with Lewy bodies and vascular disease. Multivariate statistical methods are used to determine the relative contribution of various pathological indices to cognitive function. A second and related aim is to use postmortem information to refine clinical criteria for Lewy body dementia and hippocampal sclerosis, common findings in brains of demented elderly with PA. Finally, in those brains with no significant pathology, clinicopathological correlates of cognitive slowing will be performed by analysis of inevitable age-relate granular degeneration of myelin. Imaging analysis and immunoassays for ubiquitin will be correlated with antemortem measures of cognitive processing speed.

一些认知功能完好的老年人体内有大量脑淀粉样蛋白 沉积物，老年脑淀粉样变性的一种潜在良性形式 称为“病理性老化”（PA）。其他有 PA 的科目有 认知障碍。该项目的目标是确定 PA 认知障碍的底物并确定是否 PA是临床前AD。临床病理学分析用于确定 认知障碍是否与细胞骨架和突触相关性更好 病理学上比脑淀粉样蛋白沉积更重要，这是PA的标志。 鉴于 PAD 中的淀粉样蛋白在几个方面与 AD 中的淀粉样蛋白不同， 淀粉样蛋白异质性的测量包含在定量中 评估。标准化组织病理学、生化和形态测定 测量与横断面和纵向临床相关 措施。特别是，成对螺旋丝 tau (PF-tau)、突触 使用 ELISA 测量蛋白质和特定淀粉样肽。淀粉样蛋白 和 PHF-tau“负担”也通过组织图像分析来测量 部分。 EAS 严重受损受试者需补充大脑 杰克逊维尔梅奥诊所的银行病例表明疾病进展 与进行性 PHF-tau 积累和突触损失相关，而不是 比淀粉样蛋白沉积。所有相关性均针对 载脂蛋白-A基因型。与用于“纯”AD 的检测类似的检测 PA 病例是在具有“混合”病理学的大脑上进行的，包括病例 路易体和血管疾病。多元统计方法 用于确定各种病理的相对贡献 认知功能指数。第二个相关的目标是使用 尸检信息可完善路易体痴呆的临床标准 和海马硬化，痴呆老年人大脑中的常见发现 与PA。最后，在那些没有明显病变的大脑中， 认知减慢的临床病理学相关性将通过 不可避免的与年龄相关的髓磷脂颗粒变性的分析。影像学 泛素分析和免疫测定将与生前相关 认知处理速度的测量。