Plasma Diagnostic for Alzheimer's Disease Pathology

阿尔茨海默病病理学的血浆诊断

基本信息

批准号：
6788510
负责人：
Vassilios Papadopoulos
金额：
$ 18.92万
依托单位：
SAMARITAN PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-21 至 2006-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6788510
关键词：
Alzheimer&apos s disease biomarker brain disorder diagnosis clinical research cognition dehydroepiandrosterone diagnosis design /evaluation gas chromatography mass spectrometry high performance liquid chromatography human subject iron compounds neuropathology oxidative stress phlebotomy plasma steroid hormone biosynthesis

项目摘要

DESCRIPTION (provided by applicant): Presently, there exists no simple minimally invasive test, such as a blood test, that can differentiate patients affected by Alzheimer's disease (AD) from healthy individuals. Our long-term goal is to develop new strategies for determining prognosis or predicting response to therapy. This will provide tools to improve clinical decision-making in the care of AD patients. It will also encourage individuals to test for AD early thereby maximizing opportunities for successful treatment. Our specific hypothesis is that patients with increased oxidative stress in the brain, such as AD patients, should have depleted levels of the DHEA precursor. Thus, plasma samples should contain limited levels of DHEA precursor to form DHEA in response to Fe ++ treatment. We base our hypothesis on the observations that: (1) Brain cells convert cholesterol to pregnenolone, precursor of a number of steroid modulators of neuronal functions, including DHEA, (2) DHEA biosynthesis is mediated by a cytochrome P450 17 (-hydroxylase (P450c17)-independent mechanism involving a yet unidentified hydroperoxide precursor, (3) This pathway is regulated by agents, such as Fe ++ and B-amyloid (AB) peptide, (4) DHEA levels are elevated in AD brain tissue specimens and it is formed in the AD brain by the oxidative stress-mediated metabolism of an hydroxyperoxy-steroid precursor, thus depleting the levels of the precursor present in plasma. Our specific aims are to: (1) Differentiate between the levels of DHEA precursor in the plasma of patients with AD and normal individuals. We will test for the presence of DHEA precursor in human plasma using a simple Fe ++ -based reaction and determine the amounts of DHEA formed. This simple chemical reaction will be followed by a specific and sensitive capillary gas chromatography/mass spectrometric methodology for the quantitative determination of DHEA. (2) Define the relationship between the levels of DHEA precursor in plasma and AD. We expect that the absence of the precursor in the plasma would correlate with the levels of brain oxidative stress and cognitive measures (MMSE). Should we demonstrate the DHEA precursor correlation, we can provide an early warning of oxidative stress mediated pathology, such as AD. In this Phase I application we propose to test this hypothesis in a small number of samples obtained from AD and control (non-demented) patients.

描述（由申请人提供）：目前，没有简单的微创测试，例如血液检查，可以将受阿尔茨海默氏病影响的患者与健康个体区分开。我们的长期目标是制定确定预后或预测治疗反应的新策略。这将提供改善AD患者护理的临床决策的工具。它还将鼓励个人早日测试广告，从而最大程度地获得成功治疗的机会。我们的具体假设是，大脑中氧化应激增加的患者（例如AD患者）应具有DHEA前体的水平枯竭。因此，血浆样品应包含有限水平的DHEA前体，以响应Fe ++处理而形成DHEA。我们的假设基于以下观察：（1）脑细胞将胆固醇转化为妊娠烯醇酮，这是许多神经元功能的许多类固醇调节剂的前体，包括DHEA，（2）DHEA生物合成介导的，由cytrome p450 17（-ydrosientians- p450c17）依赖性的cytrome p450介导（3）该途径受剂的调节，例如Fe ++和B淀粉样蛋白（AB）肽，（4）DHEA水平在AD脑组织标本中升高，并且通过氧化应激介导的代谢在AD脑中形成，并在AD大脑中形成了氧化毒素的代谢。区分AD患者和正常个体的血浆中的DHEA前体水平。（2）定义血浆中DHEA前体水平与AD之间的关系。我们预计血浆中的前体的不存在将与脑氧化应激和认知措施（MMSE）的水平相关。如果我们证明DHEA前体相关性，我们可以提供氧化应激介导的病理（例如AD）的预警。在此阶段I应用中，我们建议在从AD和对照（非痴呆）患者获得的少数样本中检验该假设。