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

项目总结/摘要 越来越多的证据表明，血液中维生素D水平低与痴呆症风险增加有关， 阿尔茨海默病（AD）。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，钙内流失调和谷氨酸介导的 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， 建立抗氧化和抗炎作用。最近的神经影像学研究发现， D水平与脑室周围白色病变增加、白色体积减少和 更大的心室维生素D缺乏也可能对脑功能产生不依赖于Aβ的毒性作用 新陈代谢. UC患者不同种族队列（n=382）中血清维生素D水平的初步研究 戴维斯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快速下降有关。 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决定性的 老年痴呆症风险人群的III期试验。共有180名具有纵向生物标志物的老年人， 将入组152例患者（约50例MCI，50例轻度AD， 50名无认知障碍），预计将完成为期3年半的研究。每个诊断组的一半将 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（600 IU）治疗 每日胶囊+约200 IU饮食=约800 IU/天）。纵向MRI分析将提供 治疗对脑萎缩率的影响。维生素D受体基因型多态性及其对 还将检查对口服补充剂的反应。如果补充维生素D可以改善认知能力， 结果，这可能会对公共健康产生很大影响，因为低维生素D状态是一种常见的，可读的 这可能为预防痴呆和AD提供了一个新的窗口。此外，越高 非裔美国人和拉丁美洲人中AD和痴呆的患病率可能部分归因于维生素D 不足

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.