Banik Avijit, Brown Richard E, Bamburg James, Lahiri Debomoy K, Khurana Dheeraj, Friedland Robert P, Chen Wei, Ding Ying, Mudher Amritpal, Padjen Ante L, Mukaetova-Ladinska Elizabeta, Ihara Masafumi, Srivastava Sudhir, Padma Srivastava M V, Masters Colin L, Kalaria Raj N, Anand Akshay
Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
J Alzheimers Dis. 2015;47(4):815-43. doi: 10.3233/JAD-150136.
Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
临床前研究对于转化为疾病治疗方法并在临床实践中有效应用至关重要。对阿尔茨海默病（AD）单一研究方法的过度强调似乎阻碍了该领域的转化进程，公众对缺乏有效治疗方法也颇为沮丧。我们对过去的文献（1990 - 2014年）进行了批判性回顾，分析了大量数据，并在一次关于脑老化与痴呆症的共识会议上讨论了关键问题，以识别并克服旨在转化的研究中的障碍。我们强调了影响临床前研究转化的各种因素，并突出了在临床试验中未能证明疗效的特定临床前策略。该领域一直受到AD发病机制中淀粉样蛋白假说主导的阻碍，而疾病病理学中的致病途径被广泛认为是多因素的。理解发病机制中的致病事件和机制对于转化同样重要。需要做出更大努力来填补空白，并克服动物模型的生成、研究设计、测试和评估以及未来新型抗痴呆药物试验应用中的各种混杂因素。必须考虑更多潜在的疾病机制以促进进展。
