PATHOGENESIS OF DEMENTIA--A MULTI-FACTORIAL APPROACH

虽然阿尔茨海默病（AD）的典型特征是 痴呆症与各种神经病理学特征相关， 很可能没有单一的病理变化是唯一的基础， 认知和行为障碍 在本提案中，我们 假设痴呆症的发病机制包括 定量和可变的神经元细胞体和突触损失 在多个大脑结构中同时发生， 导致痴呆症的损失，特别是当与 老化过程 为了证实痴呆症的多因素起源，我们 将识别出被诊断为 通过将他们的大脑与患有AD的人的大脑进行比较， 认知正常的老年人 将从神经元制备连续系列的组织切片。 已知与认知和行为功能有关的区域， 包括海马复合体、杏仁核、额叶的一部分， 颞叶和Meynert基底核 作为标记的 突触终端，我们将验证和扩展抗体的使用， 突触蛋白 使用这些免疫组织化学方法和标准 组织化学技术，我们将确定损失的数量和/或 突触终末和神经元细胞体的密度。 以确定 神经丧失的程度是产生痴呆症的必要和充分条件， 我们将使用一种新的方法， 图像分析系统 从第二年开始，我们将与 其他MADRC实验室通过量化来扩展数据集 AD中的药理学和生物化学损失。 我们将从统计学上 用多变量方法分析积累的数据， 表征多个位点的累积神经损失， 在AD痴呆症中。

Although Alzheimer's Disease (AD) is characterized classically by dementia associated with a variety of neuropathologic features, it is likely that there is no single pathologic change that alone is the basis for the cognitive and behavioral impairment. In this proposal, we hypothesize that the pathogenetic mechanism for dementia involves quantitative and variable neuronal cell body and synaptic losses occurring concurrently in multiple brain structures to reach a threshold of loss that results in dementia, especially when combined with the aging process. To substantiate multifactorial origins of dementia, we will identify losses that occur in the brains of patients diagnosed as having dementia due to AD by comparing them with the brains of cognitively normal aged subjects. Consecutive series of tissue sections will be prepared form neuronal regions known to be involved in cognitive and behavioral function, including the hippocampal complex, amygdala, portions of the frontal and temporal lobes, and the nucleus basalis of Meynert. As a marker of synaptic terminals, we will validate and extend the use of antibodies to synapsin. Using these immunohistochemical methods and standard histochemical techniques, we will identify losses in the number and/or density of synaptic terminals and neuronal cell bodies. To determine the extent of neural loss necessary and sufficient to produce dementia, we will quantify deficits in AD patients compared to controls using an image analysis system. Starting in year 2, we will collaborate with other MADRC laboratories to expand the data set by quantifying pharmacologic and biochemical losses in AD. We will statistically analyze the accumulated data with a multivariate approach to characterize the cumulative neural losses in multiple loci that result in the dementia of AD.