CLINICAL METABOLIC CORRELATION IN DEMENTIA BY PROTON NMR

通过质子核磁共振分析痴呆症的临床代谢相关性

• 批准号: 2675271
• 负责人: WILLIAM E KLUNK
• 金额: $ 10.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2675271
• 关键词: Alzheimer's disease; aspartate; brain metabolism; cerebral cortex; choline; creatine; gamma aminobutyrate; glutamates; glutamine; high performance liquid chromatography; hippocampus; human tissue; information systems; inositol; neuritic plaques; neurochemistry; neurofibrillary tangles; neurotoxins; nuclear magnetic resonance spectroscopy; phosphatidylethanolamines

This study proposes to perform a clinical-metabolic-neuropathological correlation in dementia, in particular, primary degenerative dementia of the Alzheimer type (AD). We will use clinical data on behavior, mood, function, and cognition obtained in the year preceding death as markers of severity. Proton nuclear magnetic resonance spectroscopy (1/H MRS) will be used to analyze 6 brain areas obtained at autopsy from 75 Alzheimer's disease (AD), 25 controls, and 15 non-AD demented controls over 5 years. The first goal is to broaden the metabolic understanding of AD and to delineate clinical-metabolic-neuropathological correlations in a way that may provide insights into the timing of pathogenetic events over the course of this dementing illness. The second goal is to provide a detailed in vitro database for future extensions of this study into 1/H MRS studies of living patients with AD. No such detailed database currently exists. The metabolites measurable by 1/H MRS include N-acetyl- L-aspartate (NAA), L-glutamate, GABA, glutamine, myo-inositol, choline- containing compounds, creative and others. NAA is important because it is a putative neuronal marker easily detected by in vitro and in vivo 1/H MRS and can give an estimate of neuronal survival. Much like senile plaques and neurofibrillary tangles, NAA can be considered a new candidate marker of the neuropathological severity of dementia. The excitatory and inhibitory amino acids also play key roles in excitotoxic theories of several dementias. The choline-containing compounds include a phosphodiester which is a product of membrane degradation. In addition to determining differences between AD and control, demented non-AD brains will be examined to determine the specificity of the changes for AD. Clinical-metabolic and metabolic-neuropathologic correlations to NAA, senile plaques, and neurofibrillary tangles will be done in an attempt to determine which changes represent early, potentially causative, events and which changes are more likely secondary effects of neurodegeneration. In addition, a separately funded study will be analyzing the tissue by 31/P MRS and the levels of the membrane metabolites, phosphomonoesters and phosphodiesters, will be available for correlative studies as well. We hypothesize that markers of membrane proliferation and neuronal inhibition will be elevated early in the disease and decreased at later stages. In contrast, markers of membrane degeneration and excitotoxicity will be elevated at later stages. Preliminary results suggest that the in vitro 1/H MRS studies proposed in this application could provide information that is valuable in both a diagnostic and pathophysiologic sense and be readily extended to non-invasive, longitudinal studies of living patients which could aid in monitoring the course of the illness and tracking efficacy of experimental therapies.

本研究建议进行临床-代谢-神经病理 痴呆症，特别是原发性退行性痴呆的相关性 阿尔茨海默型（AD）。 我们将使用行为，情绪， 功能，并在死亡前一年获得的认知作为标志， 严重性。 质子核磁共振波谱（1/H MRS）将 用于分析从75名阿尔茨海默氏症患者尸检中获得的6个脑区 疾病（AD），25名对照，15名非AD痴呆对照超过5年。 第一个目标是拓宽对AD的代谢理解， 描述临床-代谢-神经病理学相关性， 可以提供洞察的发病事件的时间超过 这一令人沮丧的疾病。 第二个目标是提供一个 本研究未来扩展至1/H的详细体外数据库 AD患者的MRS研究。 没有如此详细的数据库 目前存在。 通过1/H MRS可测量的代谢物包括N-乙酰基-N-乙酰基。 L-天冬氨酸（NAA）、L-谷氨酸、GABA、谷氨酰胺、肌醇、胆碱- 含有化合物、创意和其他。 NAA很重要，因为它是 一种易于通过体外和体内1/H MRS检测的假定神经元标记物 并且可以估计神经元的存活率。 很像老年斑 和神经元缠结的标记物，NAA可以作为一种新的候选标记物 痴呆症的神经病理学严重程度。 兴奋性和 抑制性氨基酸在兴奋性毒性理论中也起着关键作用， 几种痴呆症 含胆碱化合物包括 磷酸二酯是膜降解的产物。 除了 确定AD和对照、痴呆的非AD大脑之间的差异 将检查以确定AD变化的特异性。 临床代谢和代谢神经病理学与NAA的相关性， 老年斑和神经纤维缠结将被做， 确定哪些变化代表早期的、潜在的致病事件， 这些变化更有可能是神经退行性变的继发性影响。 在 此外，一项单独资助的研究将通过31/P分析组织， MRS和膜代谢产物磷酸单酯和 磷酸二酯也可用于相关研究。 我们 假设膜增殖和神经元抑制标记物 在疾病早期会升高，在后期会降低。 在 相比之下，膜变性和兴奋性毒性的标志物将被 在后期阶段提升。 初步结果表明，在体外 本申请中提出的1/H MRS研究可以提供信息 这在诊断和病理生理学意义上都是有价值的， 易于扩展到活体患者的非侵入性纵向研究 这可以帮助监测疾病的进程和跟踪 实验性治疗的有效性。