Thiamine Intervention and Cognition in Older Adults Undergoing Coronary Artery Bypass Grafting- A Randomized Clinical Trial

项目总结/摘要 冠心病（CHD）是一种常见的健康问题，需要超过230，500名患者接受 冠状动脉旁路移植术（CABG）每年在美国。尽管基本目标是改善 冠状动脉旁路移植术与心脏功能和增加持续时间和生活质量相关， 有害的认知变化，这可能有助于早期痴呆症和阿尔茨海默病的风险，增加 发病率、死亡率以及生活质量和社会功能下降。然而，潜在的机制 导致这种缺陷的原因尚不清楚，但可能包括应激诱导的炎症风暴和厌氧代谢。 活动高乳酸水平是无氧代谢的指标，在CABG后很常见， 这些过程可能导致CABG后认知缺陷。厌氧代谢活动可以减少， 硫胺素的输注，这是有氧代谢中必不可少的辅助因子。在缺乏足够的硫胺素的情况下 水平，丙酮酸未能进入克雷布斯循环，促进无氧代谢和增加乳酸 生产然而，目前尚不清楚是否可以使用低成本的硫胺素干预来减少CABG后 无氧活动和减少CHD受试者的认知问题。使用两组，双盲随机， 纵向研究设计，52例接受CABG的CHD患者（年龄，60-80岁; 26例接受硫胺素治疗，26例 安慰剂）将参与认知评估和血液硫胺素、乳酸盐和炎性 标记物水平。具体目的是：1）评估硫胺素治疗对血乳酸、硫胺素和 基线时接受和未接受干预的老年CHD受试者的炎症（IL-10、IL-6、IL-1β、TNF-α）水平 （5天内）和一个月后CABG; 2）检查硫胺素干预对认知的影响， 由美国国立卫生研究院认知电池，蒙特利尔认知评估，和广泛的评估， 记忆和学习2，以及有和无冠心病成人乳酸水平与认知的关系 在基线（5天内）和CABG后一个月的治疗;和3）检查硫胺素输注的效果 老年冠心病患者CABG后6个月的长期认知、生活质量和日常活动状况 接受和未接受治疗的受试者。总之，冠状动脉旁路移植术后认知障碍在CHD患者中很常见。 围手术期发生的无氧代谢活动是有害的， 缺乏和导致痴呆症和阿尔茨海默病的风险，可以减少与硫胺素输液。 硫胺素输液将促进有氧代谢，降低乳酸和炎症水平，并将服务于 作为细胞内蛋白水解和分解保护剂。这些发现有可能对 临床实践，提供证据，低成本的硫胺素干预，可以在一个大的， 大规模临床试验，以减少CABG后的认知缺陷，从而改善社会功能， 生活质量和日常活动，并降低老年CHD患者早期痴呆和阿尔茨海默病的风险。

PROJECT SUMMARY/ABSTRACT Coronary heart disease (CHD) is a common health issue, requiring over 230,500 patients to undergo coronary artery bypass grafting (CABG) each year in the USA. Despite the fundamental goal of improving function and increasing both duration and quality of life, CABG surgery is associated with increased risk of deleterious cognition changes, which may contribute to early dementia and Alzheimer’s disease risks, increased morbidity, mortality, and decreased quality of life and social function. However, the potential mechanisms contributing to such deficits remain unclear, but may include stress-induced inflammatory storm and anaerobic activities. High lactate levels, indicator of anaerobic metabolism, are common after CABG, and anaerobic processes may contribute to post-CABG cognitive deficits. Anaerobic metabolic activities can be reduced with infusion of thiamine, which is an essential co-factor in aerobic metabolism. In the absence of adequate thiamine levels, pyruvate fails to enter the Krebs cycle, promoting anaerobic metabolism and increasing lactate production. However, it is unclear whether a low-cost thiamine intervention can be used to reduce post-CABG anaerobic activities and reduce cognitive issues in CHD subjects. Using a two-group, double-blind randomized, longitudinal study design, 52 CHD patients undergoing CABG (age, 60-80 years; 26 thiamine treatment and 26 placebo) will participate for cognitive assessment and evaluation of blood thiamine, lactate, and inflammatory marker levels. The specific aims are to: 1) assess thiamine treatment effect on blood lactate, thiamine, and inflammatory (IL-10, IL-6, IL-1β, TNF-α) levels in older CHD subjects with and without intervention at baseline (within 5 days) and one month after CABG; 2) examine the effect of thiamine intervention on cognition, evaluated by the NIH Toolbox Cognition Battery, the Montreal Cognitive Assessment, and the Wide Range Assessment of Memory and Learning 2, and relationships between lactate levels and cognition in CHD adults with and without treatment at baseline (within 5 days) and one month after CABG; and 3) examine the effect of thiamine infusion after CABG on long-term cognition, quality of life, and daily activities status at 6 mo after CABG in older CHD subjects with and without treatment. In summary, post-CABG cognitive deficits are common in CHD patients. Anaerobic metabolic activities that occur during perioperative period, are deleterious introducing cognitive deficits and leading to dementia and Alzheimer’s disease risks that can be reduced with thiamine infusion. Thiamine infusion will promote aerobic metabolism and reduce lactate and inflammatory levels, and will serve as an intracellular proteolysis and breakdown protector. The findings have the potential to dramatically impact clinical practice by offering evidence for a low-cost thiamine intervention that could be implemented on a large- scale clinical trial to reduce post-CABG cognitive deficits, which could consequently improve social function and quality of life and daily activities, and reduce early dementia and Alzheimer’s disease risks in older CHD patients.