Development of a Plasma Biomarker of Alzheimer's Disease

阿尔茨海默病血浆生物标志物的开发

• 批准号: 8462809
• 负责人: MARK Anthony LOVELL
• 金额: $ 9.91万
• 依托单位: SCOUT DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2013-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462809
• 关键词: Affect; Alzheimer' s Disease; American; Animals; Autopsy; Biological Assay; Biological Markers; Blood; Brain; Cause of Death; Cerebrospinal Fluid; Clinical; Complex; Data; Dementia; Development; Diagnostic; Disease; Disease Progression; Enzymes; Etiology; Frontotemporal Dementia; Future; Immunoassay; Intervention; Left; Legal patent; Lewy Body Disease; Link; Measures; Memory; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Patients; Persons; Plasma; Prealbumin; Process; Prostaglandins; Protein Fragment; Proteins; Sampling; Sensitivity and Specificity; Serum; Specimen; Staging; Symptoms; Testing; Therapeutic Intervention; United States; Validation; base; crosslink; dimer; follow-up; hyperphosphorylated tau; mental state; mild neurocognitive impairment; nervous system disorder; neuroinflammation; neuron loss; novel; prevent; protein complex

DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective, sensitive and specific biomarker of the disease, particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this application is that plasma levels of a novel aberrant protein/protein complex consisting or lipocalin (brain-specific) prostaglandin-d- synthase (PDS) and transthyretin (TTR) are decreased early in disease progression and that baseline (pre-conversion) PDS/TTR levels are significantly lower in subjects who transition to mild cognitive impairment (MCI) or AD compared to normal control (NC) subjects or subjects with non-AD neurodegenerative disorders. As such, plasma PDS/TTR concentrations can be used to preferentially identify subjects who are likely to transition to MCI or AD. Preliminary analysis of antemortem plasma samples from 76 NC and 45 MCI subjects showed a statistically significant decrease of PDS/TTR levels in MCI. In addition, analysis of plasma PDS/TTR concentrations in normal subjects who later converted to MCI showed PDS/TTR concentrations before conversion were significantly (32 percent) lower than levels in plasma from NC subjects who remained cognitively normal during a comparable follow-up period. Although our preliminary data are promising and suggest PDS/TTR concentrations may be used to identify and predict subjects who will convert to dementia, further study is needed. To further test our hypothesis, we will analyze plasma samples from additional 80 - 100 samples from each group (NC, MCI and probable AD). We will also test whether plasma PDS/TTR complex concentrations decrease in the same person following conversion to MCI or AD by analyzing pre- and post-conversion specimens from NC subjects who transitioned from normal to MCI (n = 83) or AD (n = 32) compared to results obtained for plasma samples from control subjects who remained cognitively normal (n = 360) after a comparable follow-up period. Plasma specimens will also be analyzed from subjects with non-AD neurodegenerative diseases including frontotemporal dementia and diffuse Lewy body disease. In addition, we will test whether pre-conversion PDS/TTR concentrations alone, or in combination with A¿1-42, A¿1- 40, measures correlate with or enhance identification of MCI/AD patients based on Mini Mental State Examination (MMSE) and specific memory scores (Animal fluency, Trials A, Trials B and logical memory (logmemL)). Overall, the proposed studies, if successful, will identify and validate a novel blood based biomarker of AD that can be used to identify subjects early in disease progression when pharmacologic interventions likely have the greatest efficacy. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the sixth 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 about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this application show that a novel protein-protein complex present in serum can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD when therapeutic interventions are most likely to have beneficial effects.

描述（由应用提供）：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，缺乏该疾病的客观，敏感和特定的生物标志物，尤其是在早期阶段，当热干预措施可能具有最大效率时。该应用的基本假设是，新型异常蛋白/蛋白质复合物的血浆水平是组成或脂肪蛋白（脑特异性）前列腺素-D-合酶（PDS）和ttr蛋白（TTR）的血浆水平在疾病进展的早期降低，而在受试者的基线（conversion）中，PDS/TTR水平的差异显着降低了，而PDS/TTR水平则与WHO频率相比，与WHO频率相比， （NC）患有非AD神经退行性疾病的受试者或受试者。因此，血浆PDS/TTR浓度可用于优先识别可能过渡到MCI或AD的受试者。对来自76个NC和45名MCI受试者的天线血浆样品的初步分析显示，MCI中PDS/TTR水平的统计学显着降低。此外，对后来转化为MCI的正常受试者的血浆PDS/TTR浓度的分析显示，在转化前的PDS/TTR浓度显着（32％）明显低于NC受试者的血浆水平，而NC受试者在可比的随访期间保持正常状态。尽管我们承诺我们的初步数据，并建议使用PDS/TTR浓度来识别和预测将转化为痴呆症的受试者，但仍需要进一步研究。为了进一步检验我们的假设，我们将分析来自每组（NC，MCI和有问题AD）的其他80-100个样品的血浆样本。我们还将测试通过分析在转换为MCI或AD之后通过分析在NC受试者的转换前和转换后的分析后，同一人员的血浆PDS/TTR复合浓度是否降低，这些样本从正常情况过渡到MCI（n = 83）或AD（n = 32）（n = 32）与从对照组中获得的等离子样本相比，在n = 360上均与对照组相比获得的等离子体样本相比，该样本获得的结果是n = 360的。还将对血浆标本进行分析，包括非AD神经退行性疾病的受试者，包括额颞痴呆和弥漫性Lewy身体疾病。此外，我们将测试转换前的PDS/TTR浓度，还是与A€1-42，A�1-40结合使用，与MINI心理状态检查（MMSE）（MMSE）和特定的记忆分数（动物流动性，试验A，试验B和逻辑记忆和逻辑记忆（LOGMEML）相关或增强MCI/AD患者相关或增强MCI/AD患者的识别）。总体而言，拟议的研究（如果成功）将识别并验证一种新型的基于血液的AD生物标志物，当药物干预措施可能具有最大的效率时，可用于鉴定疾病进展的受试者。 公共卫生相关性：阿尔茨海默氏病（AD）是美国第六大死亡原因，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）缺乏对神经退行性和损失过程的了解； 2）缺乏疾病的敏感和特定的生物标志物。该应用中描述的初步研究表明，可以使用酶连接的免疫测定法（ELISA）来定量血清中存在的新型蛋白质蛋白质复合物。这种蛋白质蛋白质复合物是AD的敏感且特异性的生物标志物，包括当治疗干预措施最有益作用时，AD的早期阶段。