QUANTITATIVE INDICES OF NEURON VULNERABILITY IN DEMENTIA

阿尔茨海默病(AD)的特点是广泛的神经元死亡。 大脑皮层。这种神经元的丧失与严重的 阿尔茨海默病患者的认知和记忆功能下降。 局限于海马结构的神经病理改变是一种 一致反映与年龄相关的记忆障碍，但明显 痴呆症只出现在新皮质受累的病例中。截然不同 新皮质神经元亚群在AD时经历严重变性， 而另一些则保存得很好，即使在 疾病。因此，在联合的新皮质区域中，锥体的一个子集 神经元在阿尔茨海默病中尤其脆弱，而其他神经元类别 在AD的整个发展过程中保持存活。脆弱的神经元 它们的特点都是体型庞大，树枝状 树枝及其相对较高的神经丝蛋白含量。 进一步的研究表明，这些神经元也是 参与了神经纤维缠结(NFT)的形成，并且存在 神经丝蛋白和其他蛋白表达的年龄相关性变化 分子，如谷氨酸受体亚单位蛋白(GluRs)，可能 使神经元容易发生神经退化。然而，在多大程度上 分子和形态变化仅限于可识别的 神经元群体是反映早期反应的可靠阈值 变性或功能缺陷尚未确定。这 组件被设计用来定量分析分子和 形态相关性或功能衰退与血管病变的进展 阿尔茨海默病患者额叶上皮质神经元的改变 发展神经原纤维变性(INDS)的定量指标 基于神经元和NFT的体视学估计比率 额叶上皮质。我们还将定量地确定 已识别的皮质投射集合中GluRs的补充性 将前额叶皮质与颞叶和顶叶关联区联系起来 在猕猴身上测试这一假说 关键谷氨酸受体在下丘脑神经元之间的分布存在差异。 这些预测的来源。根据这一预测，我们将 研究阿尔茨海默病高危神经元是否表现出总体低水平 AMPA亚单位GluR2和渐进性的染色强度 AMPA和NMDA亚基表达的变化将作为神经元发生 经历退化的变化。我们假设GluR2的减少 染色强度会伴随出现的最早 在选定的AD人群中，AD中的退行性神经元变化 但不会观察到与NMDAR1的这种联系。这个 从这些研究中获得的详细的定量数据将提供 解剖和神经化学决定因素的关键信息 阿尔茨海默病的选择性神经元易损性。

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.