Subgroups of Alzheimer Disease

描述（由申请人提供）：本提案的总体目标是研究异常过度磷酸化tau的神经退行性变（阿尔茨海默病（AD）、唐氏综合征、额颞叶痴呆和其他tau蛋白病的标志性脑损伤）的发病机制中涉及的不同信号传导途径的性质，并利用该信息鉴定和诊断阿尔茨海默病的不同亚组。我们假设AD病理的产生涉及不止一种疾病机制和信号通路，并且可以根据CSF中与斑块和神经原纤维缠结相关的蛋白质水平以及在各个特定位点异常磷酸化的Taus水平来识别这种疾病的各个亚组。为了验证这一假设，我们建议（1）开发和验证用于tau蛋白各种异常磷酸化位点的超灵敏双酶循环ELISA。(2)在AD和对照病例中，使用目标#1中开发的测定法测定CSF中A β、泛素和总tau以及在各种特定位点磷酸化的tau水平，并通过聚类分析基于这些数据鉴定AD亚组。将分析APOE基因型频率和每个聚类的临床特征，包括抑郁、幻觉、运动功能减退和僵硬等症状。将测定每个磷酸化位点在适当临界点的灵敏度%和特异性%，以评价其诊断潜力。(3)目的：研究阿尔茨海默病患者脑脊液（CSF）和脑组织中可溶性和聚集性A <$1，2，泛素及各种磷酸酶水平的关系。将通过ELISA和放射免疫斑点印迹法在AD病例的冷冻尸检脑中测定可溶性和聚集的A2、泛素和各种磷酸酶的水平，其中可获得腰椎CSF。脑中这些标志物的水平将与疾病的组织病理学分期以及这些标志物的CSF水平相关。这些研究将有助于（i）根据CSF标志物鉴定AD亚组，（ii）提供有关各种亚组中涉及的信号传导途径性质的线索，（iii）揭示不同特异性位点磷酸化tau的CSF水平的诊断潜力，以及（iv）确定CSF水平与AD的关系。泛素和tau蛋白与脑中的这些标记物以及阿尔茨海默病的各种组织病理学阶段相关。从长远来看，在分子水平上对AD进行更好的分类，并鉴定代表该疾病各种亚型的潜在疾病过程的生物标志物，将改善AD和其他tau蛋白病的诊断和更好的治疗机会。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the nature of different signaling pathways involved in the etiopathogenesis of neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark brain lesion of Alzheimer disease (AD), Down syndrome, frontotemporal dementia, and other tauopathies, and employ this information to identify and diagnose the different subgroups of Alzheimer's disease. We postulate that more than one disease mechanism and signaling pathway are involved in producing AD pathology, and that various subgroups of this disease can be identified based on CSF levels of proteins associated with plaques and neurofibrillary tangles and of taus abnormally phosphorylated at various specific sites. To test this hypothesis we propose (1) to develop and validate ultrasensitive bienzyme-recycle ELISAs for various abnormal phosphorylation sites of tau. (2) To determine CSF levels of A¿, ubiquitin and total tau, and tau phosphorylated at various specific sites using the assays developed in Aim #1 in AD and control cases, and identify subgroups of AD based on these data by cluster analysis. APOE genotype frequencies and clinical profiles of each cluster, including symptoms such as depression, hallucinations, hypokinesia, and rigidity, will be analyzed. The % sensitivity and % specificity of each phosphorylation site at appropriate cut-off points will be determined to evaluate its diagnostic potential. (3) To study the relationship of levels of soluble and aggregated A¿1, 2, ubiquitin and various phosphotaus between CSF and brain in Alzheimer's disease. Levels of soluble and aggregated A¿2, ubiquitin and various phosphotaus will be assayed by ELISA and radioimmuno-dot-blots in the frozen autopsied brains of AD cases from which lumbar CSFs are available. The levels of these markers in the brain will be correlated to the histopathological staging of the disease, and to the CSF levels of these markers. These studies will help (i) identify subgroups of AD based on CSF markers, (ii) provide a lead on the nature of signaling pathways involved in various subgroups, (iii) reveal the diagnostic potential of CSF levels of tau phosphorylated at different specific sites and (iv) identify the relationship of the CSF levels of A¿, ubiquitin and tau to these markers in the brain and to the various histopathological stages of Alzheimer's disease. Better classification of AD at the molecular level and identification of biomarkers that represent the underlying disease process of various subtypes of the disease, in the long term, will lead to improved diagnosis and better defined treatment opportunities for AD and other tauopathies.