权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Profiling Alzheimer's Biomarkers

分析阿尔茨海默病的生物标志物

基本信息

批准号：
10084221
负责人：
Weiming Xia
金额：
--
依托单位：
EDITH NOURSE ROGERS MEMORIAL VETERANS HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084221
关键词：
3-Dimensional Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-42 Amyloid beta-Protein Autopsy Benchmarking Biological Biological Markers Boston Brain Cerebrospinal Fluid Clinical Cognitive Detection Disease Progression Early Diagnosis Early treatment Enzyme-Linked Immunosorbent Assay Hand Induced pluripotent stem cell derived neurons Liquid substance Mass Spectrum Analysis Measurement Measures Molecular Conformation Monitor Nature Neurofibrillary Tangles Neurons Pathogenesis Pathologic Patients Peptides Peripheral Plasma Plasma Cells Positioning Attribute Proteins Proteomics Reporting Research Personnel Sampling Senile Plaques Sensitivity and Specificity Severities Tauopathies Testing Tissues Universities Wisconsin base brain tissue candidate marker disorder control mild cognitive impairment non-demented novel marker oAβ tau Proteins tau conformation

项目摘要

Abstract With our unique multi-component clinical sample and advances in Mass Spectrometry (MS), we hope to identify a combination of multiple biomarkers that provide discriminatory and accurate biomarkers of Alzheimer’s disease (AD) to advance earlier detection and treatment. Currently, the ratio of tau/Aβ in cerebrospinal fluid (CSF) is the best available biomarker for separating AD from normal subjects and predicting disease progression, but its sensitivity and specificity are modest. Our co-investigator (co-I), Dr. Lu, discovered that a pathologic conformation, the cis-form of phosphorylated pT231-tau (cis-ptau), contributes to AD pathogenesis. Similarly, oligomeric Aβ (oAβ) is the most toxic form of Aβ to neurons, and we found that oAβ was increased in plasma and brain tissue of AD patients. Our hypothesis is that detection of increased levels of these pathologic species (cis-ptau and oAβ) will yield a robust biomarker for AD. Our team is uniquely positioned to test this hypothesis. We are the first group who reported MS-based proteomic profiling of three dimensional (3D) neuronal culture. We have analyzed candidate biomarkers from the plasma, induced pluripotent stem cells (iPSC) derived neurons, and post-mortem brain tissue from the same AD patients, which is unprecedented. We have analyzed brain tissue from 10 cases out of 20 AD, 20 MCI and 20 non-demented (ND) subjects from VA Bedford/Boston University Alzheimer Disease Center (ADC) Brain Bank (directed by co- I, Dr. Stein). Our biomarker detection capability is well-developed and we have in hand a clinically well- characterized set of plasma, CSF, and brain samples. We will validate novel biomarkers using the test samples of plasma and CSF from the same patients with early and moderate AD (20 patients) and 20 control ND subjects from Wisconsin ADC (samples are currently stored in co-I Dr. Lu’s lab). We will first determine whether CSF cis-ptau alone sufficiently separates AD from ND subjects. Next, truncated A peptides will be measured along with cis-ptau to determine whether ratios of cis-ptau/A in CSF provides a better separation of AD from ND subjects. Finally, we will quantify plasma cis-ptau and plasma oAβ, and use a combination of plasma cis-ptau and oAβ along with CSF cis-ptau as biomarkers for AD.

摘要凭借我们独特的多组分临床样品和质谱（MS）的进步，我们希望鉴定多种生物标志物的组合，所述组合提供以下生物标志物的区分性和准确性：阿尔茨海默病（AD）的早期发现和治疗。目前，tau/Aβ的比例在脑脊液（CSF）是用于将AD与正常受试者分离并预测AD发生的最佳生物标志物。疾病进展，但其敏感性和特异性适中。我们的合作研究者（co-I），陆博士，发现病理性构象，磷酸化的pT 231-tau的顺式形式（cis-ptau），有助于AD 发病机制同样，寡聚Aβ（oAβ）是Aβ对神经元毒性最大的形式，我们发现oAβ AD患者血浆和脑组织中的β-淀粉样蛋白含量均升高。我们的假设是，检测到高水平的这些病理种类（cis-ptau和oAβ）将产生AD的稳健生物标志物。我们的团队是独一无二的来检验这个假设我们是第一个报告基于MS的蛋白质组学分析的小组，三维（3D）神经元培养。我们已经分析了来自血浆的候选生物标志物，多能干细胞（iPSC）衍生的神经元，以及来自同一AD患者的死后脑组织，是史无前例的我们分析了20例AD、20例MCI和20例非痴呆患者中10例的脑组织 (ND)受试者来自VA贝德福德/波士顿大学阿尔茨海默病中心（ADC）脑库（由共同指导）， I，Dr. Stein）.我们的生物标志物检测能力是发达的，我们手头有一个临床良好的- 血浆、CSF和脑样本的特征集。我们将使用测试样本验证新的生物标志物血浆和CSF来自相同的早期和中度AD患者（20名患者）和20名对照ND 来自威斯康星州ADC的受试者（样本目前储存在co-I Dr. Lu的实验室中）。我们将首先确定单独的CSF cis-ptau是否足以将AD与ND受试者分开。接下来，将对截短的A β肽进行纯化。与cis-ptau一起沿着测量，以确定CSF中的cis-ptau/A β比率是否提供了更好的分离， ND受试者的AD。最后，我们将定量血浆cis-ptau和血浆oAβ，血浆cis-ptau和oAβ沿着CSF cis-ptau作为AD的生物标志物。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unexpected Findings During Double-blind Discontinuation of Acetylcholinesterase Inhibitor Medications.

双盲停用乙酰胆碱酯酶抑制剂药物期间的意外发现。

DOI：
10.1016/j.clinthera.2021.05.010
发表时间：
2021
期刊：
Clinical therapeutics
影响因子：
3.2
作者：
Moo,LaurenR;Martinez,Erica;Padala,Kalpana;Dunay,MeganA;Scali,RachaelR;Chen,Sunny;Thielke,StephenM
通讯作者：
Thielke,StephenM

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.