ENDOCRINE CALCIUM/PHOSPHATE REGULATION, BRAIN METABOLISM, AND ALZHEIMER'S DISEASE

内分泌钙/磷酸盐调节、大脑代谢和阿尔茨海默病

• 批准号: 6234413
• 负责人: Hartmut H Malluche
• 金额: $ 1.14万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234413
• 关键词: 1,25 dihydroxycholecalciferol; Alzheimer's disease; bioenergetics; brain metabolism; calcitonin; calcium flux; calcium metabolism; calcium phosphate; diet therapy; early diagnosis; homeostasis; hormone regulation /control mechanism; hormone therapy; human subject; human therapy evaluation; longitudinal human study; magnetic resonance imaging; nervous system disorder chemotherapy; neuropsychological tests; nutrition related tag; parathyroid hormones; pathologic process; phosphorus metabolism disorders; pituitary adrenal axis

This project is aimed at testing the hypothesis that alterations in calcium regulatory hormones and serum calcium/phosphate (Ca/PO4) homeostasis, are directly related to the etiology/pathogenesis of Alzheimer's Disease in humans. The effects of altered serum Ca/PO4 regulation on the brain could occur through chronically altered brain PO4/Ca homeostasis, through direct impact of altered peripheral hormonal patterns of actions on brain neurons (which contain vitamin D, calcitonin, glucocorticoid, and parathyroid hormone (PTH) receptors, or they may occur through aging-associated changes in Ca regulation or hormonal sensitivity at the level of the brain neuron. One interesting pathway in this context, involves the possibility that cerebral energy metabolism may be altered, possibly due to chronic subclinical hypophosphatemia and resulting hypoxia, which in turn could result in impaired Ca buffering and brain cell loss. The experimental goals of this project are few in number and relatively straightforward. However, each will be extremely time-consuming. These are to: 1) Study subjects in the very earliest stages of AD in a prospective longitudinal study that will test peripheral Ca regulation, endocrine function and cerebral energy metabolism and relate these to the onset and progression of AD over two years. Measurements will be made of the responsiveness and efficacy of four major Ca regulatory hormones (Vitamin D metabolites, adrenal-pituitary hormones, PTH and calcitonin) in relation to neuropsychological tests and magnetic resonance tests (MRI). 2) Conduct an experimental intervention test in humans diagnosed with probable AD by NIA-NINDS criteria, using a Ca regulatory hormonal treatment (1,25(OH)2-D) that is considered sufficiently safe for chronic human experimentation. Treatment would be for two years, and assessment would be by neuropsychological tests and MRI. Even partly positive results of these studies would hold major potential for both new therapeutic and new early diagnostic approaches to the problem of Alzheimer's disease.

这个项目的目的是测试钙的变化 调节激素和血清钙/磷酸盐（Ca/PO 4）稳态，是 与阿尔茨海默病的病因/发病机制直接相关， 人类 改变血清Ca/PO 4调节对大脑的影响可能 发生通过慢性改变脑PO 4/Ca稳态，通过直接 改变的外周激素作用模式对脑神经元的影响 （含有维生素D、降钙素、糖皮质激素和甲状旁腺素） 激素（PTH）受体，或者它们可能通过衰老相关的变化发生 在大脑神经元水平的钙调节或激素敏感性。 在这种情况下，一个有趣的途径，涉及的可能性， 大脑能量代谢可能会改变，可能是由于慢性 亚临床低磷酸盐血症和导致的缺氧，这反过来又可以 导致钙缓冲受损和脑细胞损失。 本项目的实验目标数量少， 直截了当。 然而，每一项都将非常耗时。 这些 是： 1)在AD的最早期阶段研究受试者， 纵向研究，将测试外周钙调节，内分泌 功能和脑能量代谢，并将这些与发病和 AD的进展超过两年。 测量将由 四种主要的钙调节激素（维生素 D代谢物、肾上腺-垂体激素、PTH和降钙素） 神经心理学测试和磁共振测试（MRI）。 2)在诊断为以下疾病的人中进行实验性干预测试： 根据NIA-NINDS标准，使用Ca调节激素治疗，可能为AD （1，25（OH）2-D），被认为对慢性人类 实验 治疗将持续两年，评估将持续两年。 通过神经心理学测试和核磁共振成像 即使这些研究的部分积极结果也具有重大潜力 新的治疗方法和新的早期诊断方法 老年痴呆症