QUANTITATIVE INDICES OF NEURON VULNERABILITY IN DEMENTIA

阿尔茨海默病（AD）的特征是在脑内广泛的神经元死亡。 大脑皮层这种神经元的损失与严重的 在AD患者中观察到认知和记忆功能下降。 仅限于海马结构的神经病理学变化是一种 一致反映年龄相关的记忆障碍，但明显 痴呆症只出现在新皮层受累的病例中。不同 新皮层神经元的亚群在AD中经历严重变性， 而另一些甚至在晚期阶段也被显着保存下来 疾病因此，在联合新皮质区的一个子集的锥体 神经元在AD中特别脆弱，而其他神经元类别 在AD的整个进展过程中保持活力。脆弱的神经元 都以它们的大尺寸、广泛的树枝状结构为特征 树枝化和相对高的神经丝蛋白含量。 进一步的研究表明，这些神经元也 参与神经纤维缠结（NFT）的形成， 与年龄相关的神经丝蛋白和其他 分子，如谷氨酸受体亚基蛋白（GluRs）， 使神经元易于发生神经变性。然而， 分子和形态学改变仅限于可识别的 神经元群体代表反映早期 退化或功能缺陷尚未确定。这 组件被设计为定量分析分子和 形态学相关或功能下降以及 AD患者上级额叶皮质神经元的改变 开发神经退行性变（IND）的定量指标 基于神经元和NFT的体视学估计的比率， 上级额叶皮层。我们还将定量地确定 确定的皮质皮质投射集合中GluRs的互补 连接前额叶皮层和颞顶叶联合区 在猕猴身上来验证一个假设 关键GluRs在神经元中的分布存在差异， 这些预测的起源。根据这一预测，我们将 研究AD风险神经元是否表现出整体低水平 AMPA亚基GluR2的染色强度和进行性 AMPA和NMDA亚基表达的变化将发生， 经历退化的变化。我们假设GluR2的减少 染色强度将伴随着最早的 AD中的退行性神经元变化，在选定的人群中， 神经元，但没有这样的协会将观察到NMDAR 1。的 从这些研究中获得的详细定量数据将提供 关键信息的解剖和神经化学决定因素 AD中的选择性神经元脆弱性。

Alzheimer's disease (AD) is characterized by extensive neuronal death in the cerebral cortex. This loss of neurons is correlated with the severe functional decline in cognition and memory observed in AD patients. Neuropathological changes restricted to the hippocampal formation are a consistent reflection of age-related memory impairment, but overt dementia is present only in cases with neocortical involvement. Distinct subpopulations of neocortical neurons undergo severe degeneration in AD, while others are remarkably preserved even at late stages of the disease. Thus, in association neocortical areas a subset of pyramidal neurons are particularly vulnerable in AD, while other neuron classes remain viable throughout the progression of AD. The vulnerable neurons are all characterized by their large size, their extensive dendritic arborization and their relatively high content of neurofilament protein. Further investigations have demonstrated that these neurons are also involved in neurofibrillary tangle (NFT) formation and that there exist age-related shifts in the expression of neurofilament protein and other molecules, such as glutamate receptor subunit proteins (GluRs), that may render a neuron prone to neurodegeneration. However, the degree to which molecular and morphological alterations restricted to identifiable neuronal populations represent reliable thresholds reflecting early degeneration or functional deficits has not yet been determined. This component is designed to analyze quantitatively the molecular and morphologic correlates or functional decline and the progression of neuronal alterations in the superior frontal cortex of AD cases by developing quantitative indices of neurofibrillary degeneration (INDs) based on ratios of stereologic estimates of neurons and NFTs in the superior frontal cortex. We will also determine quantitatively the complement of GluRs in identified sets of corticocortical projections linking the prefrontal cortex to temporal and parietal association areas in the macaque monkey to test the hypothesis that substantial differences exist in the distribution of key GluRs among the neurons of origin of these projections. Based on this prediction, we will investigate whether the neurons at risk in AD exhibit overall low staining intensity for the AMPA subunit GluR2 and that progressive shifts in AMPA and NMDA subunits expression will take place as neurons undergo degenerative changes. We hypothesize that a decrease in GluR2 staining intensity will be concomitant of the appearance of the earliest degenerative neuronal changes in AD, in a selected population of neurons, but that no such association will be observed with NMDAR1. The detailed quantitative data obtained from these studies will provide crucial information on the anatomic and neurochemical determinants of selective neuronal vulnerability in AD.