Subgroups of Alzheimer Disease

阿尔茨海默病的亚组

• 批准号: 7803578
• 负责人: KHALID IQBAL
• 金额: $ 32.98万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803578
• 关键词: Alzheimer' s Disease; Animal Model; Antibodies; Apolipoprotein E; Area; Autopsy; Biological Assay; Biological Markers; Brain; Cessation of life; Classification; Clinical; Cluster Analysis; Cytosol; Data; Dementia; Diagnosis; Diagnostic; Disease; Dot Immunoblotting; Down Syndrome; Enzyme-Linked Immunosorbent Assay; Freezing; Frequencies; Frontotemporal Dementia; Future; Generations; Genotype; Hallucinations; Heterogeneity; Hypokinesia; Immunoassay; In Vitro; Investigation; Knowledge; Lead; Lesion; Literature; Measurement; Measures; Mental Depression; Methodology; Molecular; Monitor; Monoclonal Antibodies; Morus; Muscle Rigidity; Nature; Neocortex; Neurofibrillary Tangles; Neurologic; Oryctolagus cuniculus; Outcome; Outcome Measure; Particulate; Pathology; Patients; Pattern; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Phosphorylation Site; Phosphotransferases; Procedures; Process; Protein Kinase; Proteins; Radio; Reaction; Recycling; Reporter; Research; Research Personnel; Senile Plaques; Sensitivity and Specificity; Serine; Signal Pathway; Site; Specificity; Staging; Subgroup; Symptoms; Tauopathies; Testing; Threonine; Transgenic Mice; Treatment Efficacy; Ubiquitin; Work; abnormally phosphorylated tau; base; case-based; disorder control; disorder subtype; improved; in vivo; molecular marker; mouse model; programs; self assembly; tau Proteins; tau aggregation; tau phosphorylation; tau-1

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.

描述（适用提供）：该建议的总体目的是研究与绝对磷酸化Tau神经原纤维变性有关的不同信号通路的性质，这是阿尔茨海默氏病（AD）的标志性大脑病变（AD），下降综合症，额外的dementia和其他tauopies，and tauoopies，以及其他信息，以及其他信息，以及其他信息，以及其他信息，以及其他信息，以及其他dementem declopia and tauopies，and tauopies and Information sifection inrolt of Suplotife and Information inoction inoction inoction inoction，以及不同的信息。阿尔茨海默氏病。我们假设，多种疾病机制和信号通路参与了AD病理学，并且可以根据与斑块和神经原纤维缠结相关的CSF水平来鉴定该疾病的各种亚组，以及在各个特定部位被鉴定出的taus promute promute phossute phossute磷酸化。为了检验这一假设，我们建议（1）为TAU的各种异常磷酸化位点开发和验证超敏感性生物酶循环ELISA。 （2）使用AIM＃1在AD和Control Case中开发的测定法确定A，泛素和总tau的CSF水平，并在各个特定位点磷酸化，并通过集群分析基于这些数据来识别AD的亚组。将分析每个集群的APOE基因型频率和临床谱，包括抑郁症，幻觉，低动力学和僵化等符号。每个磷酸化位点在适当的截止点上的灵敏度和百分比特异性将确定以评估其诊断潜力。 （3）研究阿尔茨海默氏病中CSF和CSF和大脑之间固体和骨料的固体和骨料的水平。 ELISA和放射免疫点印刷中的固体和聚集A检索水平将在可获得腰部CSF的AD尸体式大脑中分配。这些大脑中这些标记的水平将与疾病的组织病理学分期以及这些标记的CSF水平相关。这些研究将有助于（i）根据CSF标记确定AD的亚组，（ii）提供了有关各种亚组涉及的信号传导途径的性质，（iii）揭示了CSF在不同特定地点磷酸化的CSF磷酸化的诊断潜力，并且（IV）（iv）确定了这些标记和Tau的csf级别的ubiquitin和tau and tau和Tau的csf级别的关系。阿尔茨海默氏病。从长远来看，在分子水平上更好地对代表该疾病各种亚型的潜在疾病过程的生物标志物进行了更好的分类，这将导致改善诊断和更好定义的AD和其他tauopanty的治疗机会。