Aberrant Protein Complexes in CSF as Biomarkers of Alzheimer's Disease

脑脊液中的异常蛋白复合物作为阿尔茨海默病的生物标志物

基本信息

批准号：
7440576
负责人：
MARK Anthony LOVELL
金额：
$ 15.57万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7440576
关键词：
Affect Age Alzheimer disease prevention Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Precursor Antibodies Apolipoprotein E Autopsy Binding Proteins Biological Assay Biological Markers Buffers Cause of Death Cerebrospinal Fluid Chemicals Clinic Clinical Cognitive Communities Complex Condition Count Coupled Cuprozinc Superoxide Dismutase Data Dementia Diagnosis Diagnostic Diagnostic Procedure Diagnostic Sensitivity Disease Disease Progression Early Diagnosis Effectiveness Electrophoresis Elevation Enzyme Immunoassay Enzymes Etiology Fractionation Frontotemporal Dementia Future Gel Genotype Immunoassay Immunoprecipitation Individual Intervention Interview Laboratories Legal patent Lewy Body Disease Life Link Literature Location Mass Spectrum Analysis Measures Memory Disorders Memory Loss Modification Molecular Weight Nature Nerve Degeneration Numbers Pathogenesis Pathologic Pathology Phase Plasma Population Post-Translational Protein Processing Prealbumin Primary Health Care Process Progressive Supranuclear Palsy Prostaglandins Proteins Psyche structure Public Health Range Rate Research Retinol Binding Proteins Sampling Score Senile Plaques Sensitivity and Specificity Series Serotransferrin Specificity Specimen Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staging Staining method Stains Structure Superoxide Dismutase Testing Therapeutic Intervention Thinking Time United States Validation Ventricular Western Blotting base beta-2 Microglobulin carbonate dehydratase clinical Diagnosis cognitive function concept copper zinc superoxide dismutase improved interest liquid chromatography mass spectrometry mild neurocognitive impairment nervous system disorder neurofibrillary tangle formation neuroimaging neuropathology neuropsychological novel novel diagnostics post gamma-globulins pre-clinical prevent tandem mass spectrometry tau Proteins two-dimensional

项目摘要

DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of a sufficiently sensitive and specific objective biomarker of the disease, particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this proposal is that levels of a novel protein-protein complex present in cerebrospinal fluid (CSF) are able to differentiate AD subjects from age-matched controls and subjects with non-AD neurologic disorders. In addition, the biomarker complex appears to identify subjects with mild cognitive impairment (MCI), the earliest clinical manifestation of AD. Analysis of lumbar CSF from a small number of living probable AD and age-matched controls showed 100% sensitivity and 93% specificity in the identification of AD subjects. The proposed studies will enhance our understanding of the way in which the protein complex is generated and will further validate our initial findings by: 1) quantifying levels of the protein-protein complex in small volumes of ventricular CSF from autopsy-verified subjects with non-AD pathologies, MCI, LAD, and age-matched control subjects using an enzyme linked immunoassay developed in our laboratory based on the trapping one component of the complex and quantifying the other component ; 2) quantifying levels of the protein-protein complex in lumbar CSF from living probable AD and age-matched control subjects using the ELISA and 3) using sequential immunoprecipitation, SDS-PAGE and mass spectrometry to examine individual components of the protein complex in ventricular CSF from MCI, LAD and age-matched control subjects. Together these studies will provide further validation of our preliminary findings and will provide support for wide scale testing of the protein-protein complex as a biomarker of AD and MCI. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding of the process of neuron degeneration and loss and 2) the lack of a sufficiently sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA) and that this protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects.

描述（由申请人提供）：预防或治疗阿尔茨海默氏病（AD）的主要障碍是其未知的发病机理/病因，缺乏该疾病的足够敏感和特定的客观生物标志物，尤其是在治疗干预措施的早期阶段，可能会具有最大的效率。该提议的基本假设是，脑脊液（CSF）中存在的新型蛋白质蛋白质复合物的水平能够将AD受试者与年龄匹配的对照和患有非AD神经系统疾病的受试者区分开。此外，生物标志物复合物似乎可以鉴定出轻度认知障碍（MCI）的受试者，这是AD的最早临床表现。对少数生活可能的AD和年龄匹配的对照组对腰CSF的分析显示100％的敏感性和93％的特异性在鉴定AD受试者方面。拟议的研究将增强我们对产生蛋白质复合物的方式的理解，并将通过以下方面进一步验证我们的初步发现：1）量化较小的心室CSF中蛋白质 - 蛋白质复合物的水平，该蛋白质蛋白质复合物与非AD病理学，MCI，MCI，LAD，LAD和年龄匹配的受害者在Inszys Asspaptip中使用非AD病理学的受试者，使用Inszyme链接的型号和年龄的受试者，从而在尸检验证的受试者中使用Inszysay的Inspements Insportions Inspake In Inimun nevernecomemand和Isemants Insplate Insplate Insplate Insplate Insplations。量化其他组件； 2）使用ELISA从活着的AD和年龄匹配的对照组中量化腰CSF中蛋白质 - 蛋白质复合物的水平，3）使用顺序免疫沉淀，SDS-PAGE和质谱法检查MCI，LAD和年龄对照受试者的心室CSF中蛋白质复合物的各个成分。这些研究将共同对我们的初步发现提供进一步的验证，并将为蛋白质 - 蛋白质复合物作为AD和MCI的生物标志物的大规模测试提供支持。公共卫生相关性：阿尔茨海默氏病（AD）是美国第四大死亡原因，目前影响450万美国人。治疗和最终预防AD的两个主要障碍是：1）缺乏对神经元变性和损失过程的了解，以及2）缺乏该疾病的足够敏感和特定的生物标志物。该提案中描述的初步研究表明，可以使用酶连接的免疫测定法（ELISA）来定量脑脊液中存在的新型蛋白质蛋白质复合物（ELISA），并且该蛋白质 - 蛋白质复合物是AD的敏感和特定的AD阶段，包括AD的早期阶段（轻度认知障碍）（轻度认知障碍）（当更可能有可能产生有益的造成有益的实现）。