Supplementation with Amino Acid Rehabilitative Therapy in TBI (SmART-TBI): A Randomized Placebo-Controlled Trial to Improve Sleep

在过去，超过60%的OEF/OIF退伍军人受到轻度创伤性脑损伤的影响 十年来，这些退伍军人中有超过20%的人被诊断为脑震荡后综合征。可以说是世界上 致残的脑震荡后症状是睡眠唤醒和认知障碍。睡眠、认知功能和 相关症状通常在创伤性脑损伤后10-15年仍处于受损状态。这些症状不仅是 他们自己非常难以忍受，但睡眠和认知能力差也会干扰正在进行的 康复干预，并防止重新融入平民生活和恢复有报酬的工作。多数 现有的治疗mTBI后睡眠觉醒和认知功能障碍的方法仅仅是有症状的，它们 也存在疗效低和/或患者可接受性低的问题。因此，迫切需要确定机制-- 对mTBI后的睡眠和认知问题进行干预，以促进最佳康复 和功能结果。 我们的长期目标是实施大脑生物活性药物干预，以解决睡眠和 轻度颅脑损伤患者的认知障碍。此应用程序的总体目标代表我们的 迈向这一目标的第一步是测试一种非常有希望的疗法的可行性和有限的疗效，该疗法包括 一种膳食补充剂，支链氨基酸(即亮氨酸、异亮氨酸和缬氨酸)，用于治疗 轻度颅脑损伤患者的睡眠障碍。有令人信服的科学先例和安全数据支持 支链氨基酸治疗退伍军人合并多发脑损伤的检测我们的临床前数据表明， 支链氨基酸的作用，作为兴奋性神经递质谷氨酸的前体，恢复 对睡眠和认知功能障碍脑环内抑制的兴奋。23-26 在这些数据中，我们还精心绘制了最佳剂量、持续时间和给药途径 此外，我们现在有来自双盲、安慰剂对照研究的试点数据，显示3周 饮食中补充支链氨基酸，而不是安慰剂，显著改善了退伍军人的自我报告睡眠。 其他研究小组在多种情况下对人类使用了膳食支链氨基酸补充剂 剂量不超过60克/天，持续时间长达12个月，几乎没有副作用。 我们的中心假设是BCAA饮食补充剂将改善退伍军人的睡眠质量 MTBI。作为检验这一假设的第一步，我们提出了一个长期的可行性、可接受性和 支链氨基酸对睡眠影响的有限疗效研究将是随机、安慰剂对照和双重试验。 失明了。患有mTBI的退伍军人将被随机分配接受支链氨基酸，每次口服20、40或60克/天 (Po)或安慰剂(n=50)治疗12周。可行性、可接受性和有限的疗效结果 将根据睡眠情况进行评估(如自我报告、持续活动描记和夜间多导睡眠描记)。 我们期望这些结果将为未来的最优研究方法和设计提供参考。 规模随机对照试验，包括确定支链氨基酸的适当剂量和持续时间 改善睡眠，改善患有mTBI的退伍军人的潜在亚群，这些人群可能受到不同程度的 支链氨基酸。我们还打算利用这项工作来产生关于支链氨基酸对认知和整体的影响的假设 生活质量衡量标准为未来的研究提供信息。

Mild traumatic brain injury (mTBI) has impacted over 60% of all OEF/OIF Veterans over the past decade, and over 20% of these Veterans carry a diagnosis of postconcussion syndrome. Arguably the most disabling postconcussion symptoms are sleep-wake and cognitive disturbances. Sleep, cognitive function, and related symptoms often remain impaired >10-15 years following mTBI. Not only are these symptoms themselves exceedingly difficult to live with, but poor sleep and cognition also interfere with ongoing rehabilitation interventions, and prevent reintegration into civilian life and return to gainful employment. Most existing therapies for sleep-wake and cognitive dysfunction following mTBI are merely symptomatic, and they also suffer from low efficacy and/or patient acceptability. Thus, there is an urgent need to identify mechanism- based interventions for sleep and cognitive problems following mTBI, in order to facilitate optimal rehabilitation and functional outcomes. Our long-term goal is to implement a brain-bioactive pharmacological intervention to address sleep and cognitive disturbance in individuals with mTBI. The overall objective of this application, which represents our first step towards this goal, is to test the feasibility and limited efficacy of a highly promising therapy consisting of a dietary supplement, branched chain amino acids (BCAA; i.e., leucine, isoleucine, and valine), to treat sleep disturbances in individuals with mTBI. There is compelling scientific precedent and safety data to support the testing of BCAA therapy in Veterans with mTBI. Our preclinical data has shown that the mechanism of action for BCAA, acting as a precursor to the excitatory neurotransmitter glutamate, restores the balance of excitation to inhibition within the dysfunctional brain circuits for both sleep and cognition in mTBI.23-26 With these data, we have also meticulously mapped the optimal dosing, duration, and route of administration in mice.27 Further, we now have pilot data from a double-blinded, placebo-controlled study showing that 3 weeks of dietary BCAA supplementation, but not placebo, significantly improved self-reported sleep in Veterans. Other research groups have used dietary BCAA supplementation in humans across multiple conditions at doses up to 60 grams/day and durations up to 12 months with few to no side effects.32-49 Our central hypothesis is that BCAA dietary supplementation will improve sleep quality in Veterans with mTBI. As a first step towards testing this hypothesis, we propose a long-term feasibility, acceptability, and limited efficacy study of BCAA's effects on sleep that will be randomized, placebo-controlled, and double- blinded. Veterans with mTBI will be randomly assigned to receive BCAA at 20, 40 or 60 grams/day per oral (PO) or a placebo (n=50 per group) for 12 weeks. Feasibility, acceptability, and limited efficacy outcomes based on sleep (e.g., self-report, continuous actigraphy, and overnight polysomnography) will be assessed. We expect that these results will inform the optimal study methodology and design for a future, full- scale randomized controlled trial, including the identification of the proper dose and duration of BCAA to improve sleep and the potential subpopulations of Veterans with mTBI that may be differentially affected by BCAA. We also intend to use this work to generate hypotheses on the effect of BCAA on cognition and overall quality of life measures to inform future research.