Evaluation of a Ketogenic Diet for Improvement of Neurological Recovery in Individuals with Acute Spinal Cord Injury

摘要 尽管有广泛的研究，临床上的进步，以及更好的康复策略，脊柱 脊髓损伤(SCI)仍然是全世界残疾和死亡的重要原因，没有 药物治疗已显示出显著的改善神经功能障碍的效果。 脊髓损伤患者的功能恢复。因此，迫切需要创新 改善脊髓损伤后神经康复的治疗方法。这个项目的科学前提是建立在 越来越多的证据表明，基于饮食的疗法，如生酮饮食(KD)，提供了有效的 对继发性损伤的神经保护级联反应和改善大鼠前肢运动功能 SCI模型。KD是一种高脂肪、低碳水化合物的饮食，旨在模拟新陈代谢和 在卡路里限制期间发生的生化变化，特别是酮症。酮体有 已被证明通过减轻神经炎症和抑制发挥神经保护作用 脊髓中的细胞凋亡。因为神经炎症和诱导细胞凋亡的途径 导致损伤后不久脊髓进行性退化，抑制这些 酮体的作用可能促进脊髓损伤后神经功能的恢复。事实上，我们最近 初步研究首次表明，与标准医院饮食(SD)相比，5周的 KD能改善急性脊髓损伤患者的上肢运动功能。此外， KD患者血清中神经炎性血蛋白、纤维蛋白原低于SD患者 血清样本，提示KD可能部分通过减少 纤维蛋白原。脊髓损伤后的急性期也以高血糖为特征，这是强烈的 与出院时不良的功能结局有关。在我们的初步研究中，空腹血糖 KD组降低24 mg/dl，SD组升高0.7 mg/dl。这些 挑衅性的发现将我们引向了我们的中心假设，即使用KD的脊髓损伤患者 在受伤后的前5周(平均住院时间)，神经恢复会更好， 与服用SD的脊髓损伤患者相比，功能独立性和血糖控制更好 这段时间。我们将在一项随机对照试验中检验这一假设，目的有两个：1) 确定KD与SD的5周是否显著改善了运动和感觉功能、功能 急性脊髓损伤患者的独立性和血糖控制，以及2)定量血清生物标记物 对改善神经恢复和功能独立性负责。我们的 研究结果将揭示靶向营养策略可以 促进脊髓损伤后不久的神经康复，并可能导致安全、有效、简单和经济的 改善脊髓损伤后健康结局的干预措施。

ABSTRACT Despite extensive research, clinical advancements, and improved rehabilitation strategies, spinal cord injury (SCI) continues to be a significant cause of disability and mortality worldwide, and no pharmacologic therapy has demonstrated significant improvement effects in the neurological or functional recovery of individuals with SCI. Therefore, there is an urgent need for innovative therapies for improving neurorecovery after SCI. The scientific premise of this project builds upon accumulating evidence that diet-based therapies, such as the ketogenic diet (KD), offer effective neuroprotection against secondary injury cascades and improve forelimb motor function in a rat model of SCI. The KD is a high-fat, low-carbohydrate diet designed to mimic the metabolic and biochemical changes that occur during calorie restriction, specifically ketosis. Ketone bodies have been shown to exert neuroprotective effects by attenuating neuroinflammation and inhibiting apoptosis in the spinal cord. Because neuroinflammation and induction of apoptotic pathways lead to progressive degeneration in the spinal cord shortly after the injury, inhibition of these processes by ketone bodies may enhance neurological recovery after an SCI. Indeed, our recent pilot study showed for the first time that, compared with a standard hospital diet (SD), 5 weeks of KD improved upper extremity motor function in patients with acute SCI. In addition, levels of a neuroinflammatory blood protein, fibrinogen, were lower in the KD serum samples than in the SD serum samples, suggesting a KD may induce anti-inflammatory effects in part by reducing fibrinogen. The acute stage after SCI is also characterized by hyperglycemia, which is strongly associated with poor functional outcomes at discharge. In our pilot study, fasting serum glucose levels decreased by 24 mg/dl in the KD group but increased by 0.7 mg/dl in the SD group. These provocative findings have led us to our central hypothesis that SCI patients who consume a KD over the first 5 weeks (average hospital stay) after injury will have better neurological recovery, functional independence, and glycemic control than the SCI patients who consume an SD during this period. We will test this hypothesis in a randomized, controlled trial with two specific aims: 1) Determine if 5 weeks of KD vs. SD significantly improves motor and sensory function, functional independence, and glycemic control in patients with acute SCI, and 2) Quantify serum biomarkers that are responsible for improvements in neurological recovery and functional independence. Our findings will uncover the molecular mechanisms by which targeted nutritional strategies can promote neurorecovery shortly after SCI and may lead to a safe, effective, simple, and economical intervention that improves health outcomes after SCI.