Data_Sheet_1_Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal.pdf

BackgroundThere is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders–in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)–following a proof-of-concept study in Parkinson's disease published in 2005.
MethodsTo provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials.
Results10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class “B” evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class “U” evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class “C” evidence (possibly effective) for improvement of non-motor features and class “U” evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance.
ConclusionsLimitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.

研究背景 自2005年一项帕金森病概念验证研究发表以来，治疗性酮症作为神经退行性疾病的潜在治疗手段受到越来越多的关注，其中尤以轻度认知障碍（mild cognitive impairment, MCI）、阿尔茨海默病（Alzheimer's disease, AD）和帕金森病（Parkinson's disease, PD）为甚。

研究方法 为客观评估新兴临床证据并为未来研究提出针对性建议，本研究对2005年以来发表的、针对轻度认知障碍、阿尔茨海默病及帕金森病的生酮干预临床试验进行了系统回顾。本研究采用美国神经病学学会（American Academy of Neurology）的治疗试验评级标准，对临床证据等级进行了系统性梳理。

研究结果 本研究共纳入10项阿尔茨海默病、3项轻度认知障碍及5项帕金森病的生酮干预治疗临床试验。采用前述美国神经病学学会评级标准，对各项研究的临床证据等级进行了客观评估。结果显示：对于轻度认知障碍患者，以及载脂蛋白ε4等位基因（apolipoprotein ε4 allele, APOε4）阴性（APOε4-）的轻中度阿尔茨海默病患者，生酮干预实现认知改善的证据等级为B级（可能有效）；对于载脂蛋白ε4等位基因阳性（APOε4+）的轻中度阿尔茨海默病患者，生酮干预实现认知稳定的证据等级为U级（未证实）。针对帕金森病患者，生酮干预改善非运动症状的证据等级为C级（可能有效），而改善运动症状的证据等级为U级（未证实）。目前帕金森病相关临床试验数量较少，现有最佳证据表明，急性酮体补充有望提升运动耐力。

研究结论 现有相关研究存在一定局限性：目前文献中评估的生酮干预手段较为单一，主要集中于饮食干预或中链甘油三酯干预，采用更高效制剂（如外源性酮酯）的研究相对较少。综合来看，现有最强证据支持生酮干预可改善轻度认知障碍患者，以及APOε4-轻中度阿尔茨海默病患者的认知水平。针对上述人群开展大规模关键临床试验具有充分合理性。未来仍需开展进一步研究，以优化不同临床场景下生酮干预的应用方案，并更好地明确APOε4+患者对治疗性酮症的应答特征——此类人群可能需要调整干预策略。