von Coelln Rainer, Shulman Lisa M
Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Curr Opin Neurol. 2016 Dec;29(6):727-734. doi: 10.1097/WCO.0000000000000384.
Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years.
New and innovative clinical diagnostic criteria for Parkinson disease have been proposed and await validation. Studies using functional imaging or wearable biosensors, as well as biomarker studies, provide new support for the validity of the traditional clinical subtypes of Parkinson disease (tremor-dominant versus akinetic-rigid or postural instability/gait difficulty). A recent cluster analysis (as unbiased data-driven approach to subtyping) included a wide spectrum of nonmotor variables, and showed correlation of the proposed subtypes with disease progression in a longitudinal analysis. New genetic factors contributing to Parkinson disease susceptibility continue to be identified, including rare mutations causing monogenetic disease, common variants with small effect size and risk factors (like mutations in the gene for glucocerebrosidase) that fall in between the two other categories. Recent studies show some limited correlation between genetic factors and clinical heterogeneity. Despite some variations in patterns of pathology, Lewy bodies are still the hallmark of Parkinson disease, including the vast majority of genetic subgroups.
Evidence of clinical, genetic and pathological heterogeneity of Parkinson disease continues to emerge, but clearly defined subtypes that hold up in more than one of these domains remain elusive. For research to identify such subtypes, splitting is likely the way forward; until then, for clinical practice, lumping remains the more pragmatic approach.
近期关于帕金森病临床、遗传和病理异质性的研究，再次引发了关于帕金森病是应被视为一种具有变异的单一疾病，还是一组碰巧具有相似表型的独立疾病的古老争论。在此，我们概述了这场争论的由来，以及临床亚型、遗传学和临床病理相关性方面的最新研究结果在过去几年中如何塑造了这一争议。
已提出新的创新性帕金森病临床诊断标准并有待验证。使用功能成像或可穿戴生物传感器的研究以及生物标志物研究，为帕金森病传统临床亚型（震颤为主型与运动不能-强直型或姿势不稳/步态障碍型）的有效性提供了新的支持。最近的聚类分析（作为一种无偏的数据驱动亚型分析方法）纳入了广泛的非运动变量，并在纵向分析中显示所提出的亚型与疾病进展相关。导致帕金森病易感性的新遗传因素不断被发现，包括导致单基因疾病的罕见突变、效应大小较小的常见变异以及介于其他两类之间的风险因素（如葡萄糖脑苷脂酶基因突变）。近期研究表明遗传因素与临床异质性之间存在一些有限的相关性。尽管病理模式存在一些差异，但路易小体仍是帕金森病的标志，包括绝大多数遗传亚组。
帕金森病临床、遗传和病理异质性的证据不断涌现，但在这些领域中不止一个领域得到验证的明确亚型仍然难以捉摸。对于识别此类亚型的研究而言，分类可能是前进的方向；在此之前，对于临床实践来说，合并仍然是更务实的方法。
