Cummings Jeffrey L
Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Departments of Neurology and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Alzheimers Dement. 2009 Sep;5(5):406-18. doi: 10.1016/j.jalz.2008.12.003.
Alzheimer's disease (AD) might be treated with symptomatic, neuroprotective, or neurorestorative therapies. Neuroprotective and neurorestorative interventions are disease-modifying therapies. Disease modification can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of AD. In a clinical trial the criteria for affecting the underlying cause of the disease can be supported by demonstrating an effect on a biomarker such as medial temporal atrophy on magnetic resonance imaging (MRI) or diminished tau or phospho-tau levels in cerebrospinal fluid. The claim for a beneficial effect on the clinical course of AD is supported by a drug-placebo difference on the primary clinical outcomes of the clinical trial. A statistically significant correlation between the biomarker outcome and the clinical trial outcome would support the claim that these are based on the same underlying mechanism. Delayed start or staggered withdrawal designs might in themselves support a disease-modifying claim but are difficult to implement. A combination of clinical outcomes and biomarker measures is a more likely pathway to a disease-modifying claim. Labeling of disease-modifying agents might refer to slowing of disease progression, delay in reaching predefined disease milestones, or reduction in progression of a biomarker such as cerebral atrophy or ventricular enlargement on MRI. Prevention claims will depend heavily on biomarker outcomes.
阿尔茨海默病（AD）或许可以通过对症治疗、神经保护治疗或神经修复治疗来进行干预。神经保护和神经修复干预属于疾病修饰疗法。疾病修饰可定义为影响疾病潜在病理生理学并对AD病程产生有益结果的治疗或干预措施。在一项临床试验中，影响疾病根本病因的标准可通过证明对生物标志物有影响来支持，比如磁共振成像（MRI）显示的内侧颞叶萎缩，或脑脊液中tau或磷酸化tau水平降低。对AD临床病程产生有益效果的说法可通过临床试验主要临床结局上的药物 - 安慰剂差异来支持。生物标志物结局与临床试验结局之间具有统计学意义的相关性将支持这样的说法，即它们基于相同的潜在机制。延迟启动或交错撤药设计本身或许能支持疾病修饰的说法，但难以实施。临床结局与生物标志物测量结果相结合是获得疾病修饰说法更有可能的途径。疾病修饰药物的标签可能提及疾病进展的减缓、达到预定义疾病里程碑的延迟，或生物标志物进展的减少，如MRI上脑萎缩或脑室扩大。预防说法将在很大程度上依赖生物标志物结局。
