Phase II RCT of High-dose Vitamin D Supplements in Older Adults without Dementia

大剂量维生素 D 补充剂治疗无痴呆症老年人的 II 期随机对照试验

• 批准号: 9751690
• 负责人: John M Olichney
• 金额: $ 95.06万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751690
• 关键词: Abeta clearance; African American; Age; Alzheimer' s Disease; Amyloid beta-Protein; Antiinflammatory Effect; Antioxidants; Biological Markers; Blood; Brain; Brain region; Calcium; Caucasians; Cholecalciferol; Cognitive; Communities; Data; Dementia; Diagnostic; Diet; Dose; Effectiveness; Elderly; Enrollment; Episodic memory; Genetic Polymorphism; Genotype; Glutamates; High Prevalence; Hippocampus (Brain); Hispanics; Impaired cognition; Intake; Intervention; Latino; Low Prevalence; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Neuropsychological Tests; Oral; Outcome; Oxidative Stress; Pathology; Persons; Phase; Prevention; Public Health; Publishing; Randomized; Randomized Clinical Trials; Readability; Risk; Serum; Study of serum; Supplementation; Testing; Toxic effect; Urine; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D3 Receptor; White Matter Disease; aging brain; base; capsule; cerebral atrophy; cognitive change; cognitive function; cohort; compare effectiveness; dementia risk; design; ethnic diversity; executive function; improved; inflammatory marker; neuroimaging; neurotoxicity; novel; oral supplementation; phase 3 study; phase III trial; prevent; primary outcome; receptor; response; treatment effect; white matter

Project Summary/Abstract There is mounting evidence that low vitamin D blood levels are associated with increased risk of dementia and Alzheimer's disease (AD). There are several mechanisms by which low vitamin D status may promote AD pathology, including reduced β-amyloid (Aβ) clearance, dysregulation of calcium influx and glutamate- mediated neurotoxicity. Vitamin D interacts with receptors in the hippocampus and many other brain regions, and has established antioxidant and anti-inflammatory effects. Recent neuroimaging studies have found that low vitamin D levels are associated with increased periventricular white matter disease, reduced white matter volume and larger ventricles. Vitamin D deficiency may also have a toxic effect on brain function independent of Aβ metabolism. Preliminary studies of serum vitamin D levels in a diverse multi-ethnic cohort (n=382) of the UC Davis Alzheimer's Disease Center found a high prevalence of low vitamin D status (61% with levels <20 ng/ml), which was associated with faster rates of decline on executive function and episodic memory. This Phase II randomized clinical trial aims to test if supplementation with high dose oral vitamin D will successfully correct vitamin D insufficiency, compared to treatment with standard (RDA) dose vitamin D in a diverse community-based elderly cohort. The effect of high-dose vs. standard-dose vitamin D on altering cognitive trajectories will also be assessed and data will be expected to be used in designing a potential definitive Phase III trial in elderly groups at risk for dementia. A total of 180 elderly persons with longitudinal biomarkers, neuropsychological testing and brain MRI scans will be enrolled, with 152 (~50 with MCI, 50 with mild AD and 50 with no cognitive impairment) expected to complete the 3½-year study. One-half of each diagnostic group will be randomized to treatment with high-dose vitamin D3 (4,000 IU daily) or to standard dose Vitamin D (600 IU capsule daily + ~200 IU dietary = ~800 IU total/day). Longitudinal MRI analyses will provide an estimate of the treatment effect size on brain atrophy rate. Vitamin D receptor genotype polymorphisms and their impact on response to oral supplementation will also be examined. If vitamin D supplementation improves cognitive outcome, this could have a large impact on the public health, since low vitamin D status is a common, readably treatable condition which may provide a novel window to prevent dementia and AD. Furthermore, the higher prevalence of AD and dementia in African Americans and Latinos could be partially attributable to vitamin D insufficiency.

项目总结/摘要 越来越多的证据表明，低维生素D血液水平与痴呆症和阿尔茨海默病（AD）的风险增加有关。有几种机制，低维生素D状态可能会促进AD 病理学，包括β-淀粉样蛋白（Aβ）清除率降低，钙内流和谷氨酸- 介导的神经毒性。维生素D与海马体和许多其他大脑区域的受体相互作用， 并具有抗氧化和抗炎作用。最近的神经影像学研究发现， 低维生素D水平与脑室周围白色疾病增加、白色减少 体积和更大的心室。维生素D缺乏也可能对大脑功能产生毒性作用， Aβ代谢。在一个不同种族的队列（n=382）中对血清维生素D水平的初步研究， 加州大学戴维斯分校阿尔茨海默病中心发现，低维生素D状态的患病率很高（61%的水平<20 ng/ml），这与执行功能和情景记忆的下降速度更快有关。 这项II期随机临床试验旨在测试补充高剂量口服维生素D是否会 成功纠正维生素D不足，与标准（RDA）剂量维生素D治疗相比， 以社区为基础的多样化老年群体。高剂量与标准剂量维生素D对改变 认知轨迹也将被评估，数据将被用于设计一个潜在的 在有痴呆风险的老年人群中进行的确定性III期试验。共180名长者， 将入组152例患者（约50例患有MCI，50例患有 轻度AD和50名无认知障碍），预计将完成为期3年半的研究。各一半 诊断组将随机接受高剂量维生素D3（每日4，000 IU）或标准 剂量维生素D（每日600 IU胶囊+约200 IU膳食=约800 IU/天）。纵向MRI分析将 提供对脑萎缩率的治疗效应量估计值。维生素D受体基因 还将检查多态性及其对口服补充剂反应的影响。如果维生素D 补充改善认知结果，这可能对公共健康产生重大影响，因为低 维生素D状态是一种常见的，可治疗的疾病，这可能提供了一个新的窗口，以防止 痴呆和AD。此外，非裔美国人和拉丁美洲人中AD和痴呆症的患病率较高， 可能部分归因于维生素D不足。