Plasma Diagnostic for Alzheimer's Disease Pathology

描述（由申请人提供）：目前，没有简单的微创检查，如血液检查，可以区分阿尔茨海默病（AD）患者与健康个体。我们的长期目标是开发确定预后或预测治疗反应的新策略。这将为改善阿尔茨海默病患者护理的临床决策提供工具。它还将鼓励个人尽早检测阿尔茨海默病，从而最大限度地提高成功治疗的机会。我们的具体假设是，大脑中氧化应激增加的患者，如AD患者，应该已经耗尽了脱氢表雄酮前体的水平。因此，血浆样品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Fe ++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，这是许多神经元功能类固醇调节剂的前体，包括脱氢表雄酮（DHEA）；(2)脱氢表雄酮的生物合成是由细胞色素p45017(-羟化酶（P450c17）独立机制介导的，涉及尚未确定的过氧化氢前体；(3)这一途径受铁++和b -淀粉样蛋白（AB）肽等药物调节。(4)脱氢表雄酮水平在阿尔茨海默病脑组织标本中升高，它是在阿尔茨海默病大脑中通过氧化应激介导的羟基过氧化物类固醇前体代谢而形成的，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。我们将使用一个简单的基于Fe ++的反应来测试人血浆中脱氢表雄酮前体的存在，并确定形成的脱氢表雄酮的量。这个简单的化学反应之后，将有一个特定的和敏感的毛细管气相色谱/质谱方法用于DHEA的定量测定。(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失将与大脑氧化应激和认知测量（MMSE）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，如AD的早期预警。在这个I期应用中，我们建议在从AD和对照（非痴呆）患者中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.