Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, 575 Patterson Ave, Winston-Salem, NC, 27101, USA.
Salisbury VA Medical Center, Salisbury, NC, 28144, USA.
Geroscience. 2024 Feb;46(1):665-682. doi: 10.1007/s11357-023-00999-9. Epub 2023 Nov 23.
Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888.
烟酰胺核糖（NR）可提高烟酰胺腺嘌呤二核苷酸（NAD+）的血液水平，NAD+是能量代谢的核心辅因子，并可改善某些神经退行性变啮齿动物模型的大脑功能。我们进行了一项安慰剂对照随机试点研究，主要目的是确定烟酰胺核糖（NR）在轻度认知障碍（MCI）老年患者中的安全性。20 名 MCI 患者被随机分配接受安慰剂或 NR 治疗，通过剂量递增达到并维持 10 周研究期间每天 1 克的最终剂量。主要结局是从基线认知测量（蒙特利尔认知评估，MoCA）中治疗后的变化。预先确定的次要结局包括治疗后大脑血液流量（CBF）的变化；血液 NAD+水平；以及其他神经认知、心理测量和身体表现测试。外周血单核细胞（PBMC）中的 DNA 甲基化作为探索性结局进行评估。NR 组的血液 NAD+水平增加了 2.6 倍（p < 0.001，95%CI [17.77，43.49]），证明达到了目标 NR 剂量，并且没有报告组间不良事件的差异。MoCA 和其他神经认知和心理测量指标在整个研究过程中保持稳定。NR 降低了默认模式网络（DMN）中的 CBF，左顶下小叶（IPL）的差异最大（DMN p = 0.013，μ = 0.92，95%CI [0.23，1.62]；左 IPL p = 0.009，μ = 1.66，95%CI [0.5，2.82]）。安慰剂组的步行速度在整个研究期间显著提高，提示存在练习效应，但 NR 组的步行速度没有变化（p = 0.0402 和 p = 0.4698）。其他次要结局指标保持稳定。全基因组甲基化分析表明，NR 与 DNA 甲基化的适度增加相关，并通过 PhenoAge 和 GrimAge 表观遗传时钟分析测量，与表观遗传年龄降低相关。总之，NR 可显著增加 MCI 老年患者的血液 NAD+浓度。NR 耐受性良好，不会改变认知。虽然 NR 治疗降低了 CBF，但统计学意义不会经受多次比较校正的考验。需要进行更长时间的更大规模试验，以确定 NR 作为改善认知和改变 MCI 老年患者 CBF 的策略的潜力。ClinicalTrials.gov NCT02942888。
