Plasma Diagnostic for Alzheimer's Disease Pathology

描述(申请人提供)：目前，还没有简单的微创测试，如血液测试，可以区分阿尔茨海默病(AD)患者和健康人。我们的长期目标是开发新的策略来确定预后或预测治疗反应。这将为改善AD患者护理的临床决策提供工具。它还将鼓励个人及早检测AD，从而最大限度地增加成功治疗的机会。我们的特定假设是，大脑中氧化应激增加的患者，如AD患者，应该有DHEA前体的枯竭水平。因此，血浆样本应含有有限水平的脱氢表雄酮前体，以形成脱氢表雄酮，以响应铁处理。我们的假设基于以下观察：(1)脑细胞将胆固醇转化为孕烯醇酮，这是包括DHEA在内的许多神经功能类固醇调节剂的前体，(2)DHEA的生物合成是由细胞色素P450 17(-羟基酶，P450c17)非依赖的机制介导的，涉及一种未知的过氧化氢前体，(3)这一途径受到铁和B-淀粉样蛋白(AB)肽等药物的调节，(4)在AD脑组织标本中DHEA水平升高，它是通过羟基过氧化应激前体的氧化应激代谢在AD脑中形成的。从而耗尽了血浆中存在的前体的水平。我们的具体目的是：(1)区分AD患者和正常人血浆中DHEA前体的水平。我们将使用一个简单的基于铁的反应来测试人体血浆中是否存在DHEA前体，并确定生成的DHEA的数量。在这一简单的化学反应之后，将建立一种特异和灵敏的毛细管气相色谱/质谱方法来定量测定DHEA。(2)明确血浆DHEA前体水平与AD的关系。我们预计，血浆中前体的缺乏将与大脑氧化应激和认知测量(MMSE)的水平相关。如果我们证明脱氢表雄酮前体的相关性，我们可以提供氧化应激介导的病理的早期预警，如AD。在这个第一阶段的应用中，我们建议在从AD患者和对照(非痴呆)患者获得的少量样本中检验这一假设。

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.