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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，如血液测试，可以区分受阿尔茨海默病（AD）影响的患者与健康个体。我们的长期目标是开发新的策略来确定预后或预测对治疗的反应。这将为改善AD患者护理的临床决策提供工具。它还将鼓励个人早期检测AD，从而最大限度地增加成功治疗的机会。我们的具体假设是，大脑中氧化应激增加的患者，如AD患者，应该已经耗尽了DHEA前体的水平。因此，血浆样品应含有有限水平的DHEA前体，以响应Fe ++处理形成DHEA。我们的假设基于以下观察结果：（1）脑细胞将胆固醇转化为胆固醇烯醇酮，胆固醇烯醇酮是许多神经功能类固醇调节剂的前体，包括DHEA，（2）DHEA生物合成由细胞色素P450介导17 β-羟化酶（P450 c17）-非依赖性机制，涉及尚未鉴定的氢过氧化物前体，（3）该途径受试剂调节，例如Fe ++和B-淀粉样蛋白（AB）肽，（4）AD脑组织样本中DHEA水平升高，并且它是通过氧化应激介导的羟基过氧类固醇前体代谢在AD脑中形成的，从而耗尽血浆中存在的前体水平。我们的具体目标是：（1）区分AD患者和正常人血浆中DHEA前体的水平。我们将使用简单的基于Fe ++的反应测试人血浆中DHEA前体的存在，并确定形成的DHEA的量。这个简单的化学反应之后，将由一个特定的和敏感的毛细管气相色谱/质谱法定量测定DHEA。(2)明确血浆DHEA前体水平与AD的关系。我们预期血浆中前体的缺乏将与脑氧化应激和认知测量（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学（如AD）的早期预警。在这个I期申请中，我们建议在从AD和对照（非痴呆）患者获得的少量样本中测试这一假设。