Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.
Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.
复制标题
DOI：
10.1002/mds.26913
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Lang AE
中科院分区：
文献类型：
--
作者：
Espay AJ;Schwarzschild MA;Tanner CM;Fernandez HH;Simon DK;Leverenz JB;Merola A;Chen-Plotkin A;Brundin P;Kauffman MA;Erro R;Kieburtz K;Woo D;Macklin EA;Standaert DG;Lang AE
过去的临床试验推定的神经保护疗法有针对性的帕金森病（PD）作为一个单一的致病性疾病实体。从奥斯勒临床病理学的角度来看，广泛的复杂性PD收敛到路易体，并证明了一个简化的方法PD：一个单一的机制治疗可以影响大多数共享的经典病理标志。从系统生物学的角度来看，PD是一组疾病，虽然通过共享黑质多巴胺神经元变性的特征而相关，但表现出独特的遗传，生物学和分子异常，这可能对给定的治疗方法产生差异反应，特别是针对神经保护的策略。在这种模型下，只有生物标志物定义的同质亚型的PD可能对被证明影响每种亚型内生物学过程的疗法有最佳反应。因此，我们认为，应用于PD的精准医学需要重新评估生物标志物发现的努力。这项工作目前集中在相关的生物措施，PD的临床特征和识别因素，预测是否各种前驱状态将转化为经典的运动障碍。相反，我们认为PD的亚型需要相反的观点，即异常的生物信号（即，生物标志物）而不是临床定义用于定义疾病表型。疾病修饰策略的成功开发将取决于干预措施所解决的特定生物过程与目标患者亚组中的发病机制的相关程度。这种精确的医学方法可能会产生较小但定义明确的PD子集，这些子集可以成功地进行神经保护。
Past clinical trials of putative neuroprotective therapies have targeted Parkinson disease (PD) as a single pathogenic disease entity. From an Oslerian clinico-pathologic perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: a single-mechanism therapy can affect most of those sharing the classic pathologic hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers) rather than clinical definitions are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller but well-defined subsets of PD amenable to successful neuroprotection.