MONOAMINES IN ALZHEIMER'S DISEASE/COULOMETRIC DETECTION

阿尔茨海默病中的单胺/库仑检测

• 批准号: 3117452
• 负责人: LADISLAV VOLICER
• 金额: $ 15.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3117452
• 关键词: 3,4 dihydroxyphenylacetate; 5 hydroxytryptophan; Alzheimer's disease; brain disorder diagnosis; cerebrospinal fluid; coulometry; electrochemistry; high performance liquid chromatography; homovanillate; human tissue; hydroxyindoleacetate; neurochemistry; neurotoxins; neurotransmitter metabolism; norepinephrine; oxidation reduction reaction; postmortem; serotonin

Despite recent advances in our understanding of dementia of Alzheimer type (DAT) its etiology is still unknown. It is not known if the cholinergic deficit, detected in most DAT patients, is the primary pathological process or a consequence of other processes. There is considerable evidence indicating involvement of neurotransmitters other than acetylcholine in DAT. We have found a strong evidence for involvement of the dopaminergic and serotoninergic systems and would like to continue this investigation. This work will include application of a new approach to electrochemical detection of substances in cerebrospinal fluid (CSF). This detection involves use of multiple coulometric electrodes which are set at different voltages. We have a preliminary evidence indicating that liquid chromatography using amperometric detection leads to erroneously high estimates of CSF concentrations of DOPAC, HVA, MHPG, 5-HT and 5-HIAA. This error is due to presence of co-eluting interfering compounds which are indistinguishable by the amperometric method but can be differentiated from the authentic monoamine metabolites by the use of coulometric gates and multiple sensors. In addition to the coulometric method is more sensitive than the amperometric one and allows detection of norepinephrine, epinephrine and dopamine in CSF. Investigation with a 6-sensor system coulometric system also indicated presence of 5-HTP and 5-HT in a form which had already undergone oxidation of the 5-hydroxy group, presumably to the quinone. The partially oxidized 5-HT (5-HT-e) in DAT CSF is not metabolized by monomine oxidase. This could explain the aberrant relationship of 5-HT and 5-HIAA levels in rostral fraction of DAT CSF found by us previously. It is possible that 5-HT-e- participates in pathogenesis of DAT, since the neurotoxic effect of 6-hydroxy-dopamine is mediated by formation of a quinone intermediate. In this project we will investigate monoamines and their metabolites, as well as the abnormal form of 5-HT and other interfering substances, using an advanced version of the multidetector coulometric system. We plan to investigate these compounds and compare them in CSF from controls and DAT patients. The presence of a specific change of monoamine concentration or a specific interfering compound would provide not only a diagnostic procedure for DAT but it would give us also a clue for the pathogenesis of DAT. The possible role of 5-HT-e- in DAT will be tested by measuring 5-HT-e- in DAT brains and by investigation of 5-HT-e-neurotoxicity.

尽管我们了解阿尔茨海默氏症类型痴呆症的最新进展 （DAT）其病因仍然未知。 尚不清楚胆碱能是否 在大多数DAT患者中检测到的赤字是主要病理过程 或其他过程的结果。 有大量证据 表明除乙酰胆碱以外的神经递质参与 dat。 我们找到了有力的多巴胺能参与的证据 和5-羟色胺能系统，并希望继续进行这项调查。 这项工作将包括采用新方法来进行电化学 检测脑脊液（CSF）中的物质。 此检测 涉及使用多个库米电极，这些电极设置为不同 电压。 我们有初步证据，表明液体 使用安培检测的色谱法导致错误高 DOPAC，HVA，MHPG，5-HT和5-HIAA的CSF浓度的估计值。 这 错误是由于存在共同洗脱的干扰化合物 通过安培方法无法区分，但可以区分 通过使用coulometric大门和 多个传感器。 除了库尔仪法更敏感 比安培计量学，允许检测去甲肾上腺素， CSF中的肾上腺素和多巴胺。 对6传感器系统库米系统的调查也表示 以已经经过氧化的形式存在5-HTP和5-HT 5-羟基群，大概是喹酮。 部分氧化 DAT CSF中的5-HT（5-HT-E）未被单氧化酶代谢。 这 可以解释5-HT和5-HIAA水平的异常关系 我们以前发现的DAT CSF的鼻ro骨部分。 有可能 5-HT-E-参与DAT的发病机理，因为 6-羟基丙氨酸是通过形成喹酮中间体介导的。 在这个项目中，我们将调查单胺及其代谢产物，作为 以及5-HT和其他干扰物质的异常形式，使用 多探测器库米系统的高级版本。 我们计划 研究这些化合物并通过控件和DAT中的CSF进行比较 患者。 单胺浓度的特定变化或 特定的干扰化合物不仅可以提供诊断 DAT的过程，但这也将为我们提供有关的发病机理的线索 dat。 5-HT-E-在DAT中的可能作用将通过测量测试 5-HT-E-在DAT大脑中，并通过研究5-HT-E-神经毒性。