ALZHEIMERS DISEASE AS A SYSTEMIC DISORDER

阿尔茨海默病是一种全身性疾病

• 批准号: 6168018
• 负责人: THOMAS F. BUDINGER
• 金额: $ 26.52万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-05-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168018
• 关键词: Alzheimer's disease; acetylcholine; adenosine triphosphate; bioenergetics; brain circulation; carbohydrate metabolism; cerebral ischemia /hypoxia; clinical research; deoxyglucose; glucose metabolism; glucose transport; human subject; hydrogen transporting ATP synthase; leukocytes; nuclear magnetic resonance spectroscopy; nutrient intake activity; nutrition related tag; oxidative phosphorylation; pharmacokinetics; physostigmine; positron emission tomography; striated muscles; ultrasound blood flow measurement; vascular endothelium; vasodilatation

DESCRIPTION: (Adapted from applicant's abstract): This grant proposes to explore the hypothesis that Alzheimer's disease (AD) is a systemic disease caused by a chronic ATP deficiency resulting from diminished blood flow reactivity or defective glucose metabolism. Progressive damage to the nonregenerative central nervous system neurons is manifested early in the CNS because of the susceptibility of neurons to low blood flow and the limited ability of neurons to regenerate and to maintain mitochondrial enzymes. Specifically, we will investigate the role of systemic perfusion reactivity and systemic carbohydrate metabolism in AD. These hypotheses will be tested by experimental protocols including: (1) measurement of the deficit in acetylcholine neurons in AD by quantification of physostigmine stimulation of cerebral blood flow using high resolution PET with 122I-HIPDM; (2) measurement of endothelium-dependent vasodilatation of peripheral limb resistance vessels in AD patients in response to tourniquet-induced (blood pressure cuff) ischemia using a Doppler analysis method developed in previous; (3) evaluation of kinetics of 18F-fluorodeoxyglucose in exercising skeletal muscle of AD using positron emission tomography; (4) in vivo 4T magnetic resonance studies of oxidative phosphorylation potential in AD patients' (5) in vitro glucose metabolism studies using 14C glucose in leukocytes; and (6) mitochondrial function assays of leukocytes in AD and controls. This proposal involves 284 different patients and subjects in 405 in vivo and in vitro non-invasive studies. The procedures are currently validated technologies using unique resources at Lawrence Berkeley National Laboratory. New critical experiments in this proposal are the method of performing in vivo studies of peripheral vessel relaxivity, the in vivo skeletal muscle metabolism studies using FDG-PET, and the in vivo skeletal muscle oxidative phosphorylation potential studies utilizing 4T magnetic resonance spectroscopy.

描述：（改编自申请人的摘要）：本补助金旨在 探讨阿尔茨海默病（AD）是一种全身性疾病的假设 由于血液流动减少而导致的慢性ATP缺乏引起的 反应性或葡萄糖代谢缺陷。逐渐损坏 非再生性中枢神经系统神经元在CNS早期表现为 由于神经元对低血流量的敏感性和有限的 神经元再生和维持线粒体酶的能力。 具体来说，我们将研究全身灌注反应性的作用， AD中全身糖代谢。这些假设将由以下人员进行检验： 实验方案包括：（1）测量 通过量化毒扁豆碱刺激AD中的乙酰胆碱神经元， 脑血流量的高分辨率PET与122 I-HIPDM;（2）测量 外周肢体阻力血管的内皮依赖性血管舒张 AD患者对止血带诱导（血压袖带）缺血的反应 利用多普勒分析方法在以前开发的;（3）评价 18F-氟脱氧葡萄糖在AD运动骨骼肌中的动力学 正电子发射断层扫描;（4）体内4 T磁共振研究， AD患者的氧化磷酸化潜力（5）体外葡萄糖 在白细胞中使用14 C葡萄糖的代谢研究;和（6）线粒体 AD和对照中白细胞的功能测定。 该提案涉及284名不同的患者和受试者在405个体内， 体外非侵入性研究。这些程序目前已得到确认 劳伦斯伯克利国家实验室利用独特的资源。 新的关键实验在这个建议是在体内进行的方法， 外周血管舒张性、体内骨骼肌代谢的研究 使用FDG-PET的研究，以及体内骨骼肌氧化 使用4 T磁共振光谱进行磷酸化潜力研究。