Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression
Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression
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DOI：
10.1093/brain/awx118
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发表时间：
2017-07-01
期刊：
影响因子：
14.5
通讯作者：
Postuma, Ronald B.
中科院分区：
文献类型：
--
作者：
Fereshtehnejad, Seyed-Mohammad;Zeighami, Yashar;Postuma, Ronald B.
帕金森病的临床表现、进展过程和生物标志物特征因人而异。识别不同的帕金森病亚型对于阐明潜在的病理生理学、预测进展和开发更有效的个性化护理方法至关重要。目前尚无明确的方法来定义和划分帕金森病的亚型。利用帕金森病进展标记计划的数据，我们的目的是通过对由临床特征、神经影像、生物样本和遗传信息组成的基线综合数据集（即横截面）进行聚类分析来识别不同的亚组，然后制定将患者分配到帕金森病亚型的标准。这个前瞻性纵向多中心队列包括 421 名患有新发早期帕金森病的个体。使用人口和遗传信息、运动症状和体征、神经心理学测试和其他非运动表现的数据进行层次聚类分析。聚类分析中的关键分类是运动总结评分和三个非运动特征（认知障碍、快速眼动睡眠行为障碍和自主神经功能障碍）。然后，我们定义了帕金森病患者的三种不同亚型：223 名患者被分类为“轻度运动为主”（定义为复合运动和所有三个非运动评分低于 75%），52 名患者被分类为“弥漫性恶性”（综合运动评分加上 51/3 非运动评分第 475 个百分位，或所有三个非运动评分都为第 475 个百分位），146 名患者被分类为“中间'。在生物标志物上，弥漫性恶性帕金森病患者的脑脊液淀粉样蛋白-b 水平最低（329.0 +/- 96.7 pg/ml，P = 0.006），淀粉样蛋白-b/总 tau 比率（8.2 +/- 3.0，P = 0.032）最低。基于变形的磁共振成像形态测定数据表明，帕金森病特异性脑网络在弥漫性恶性亚型中萎缩较多，而轻度运动为主的亚型萎缩最少。尽管不同亚型的初次就诊和随访时间相似，但弥漫性恶性帕金森病患者的总体预后（总体综合结果）进展更快，平均 2.7 年后认知和多巴胺功能神经影像学下降幅度更大。总之，我们根据临床表现和生物标志物的综合列表，引入了帕金森病亚型的新临床标准。现在可以使用基线临床信息将这种临床亚型应用于个体患者，以便在临床实践中使用。尽管所有参与者最近都被诊断为帕金森病，但弥漫性恶性亚型患者已经表现出更严重的多巴胺能缺陷、帕金森病大脑网络萎缩加剧、脑脊液特征更类似于阿尔茨海默病以及运动和认知缺陷进展更快。
Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either 51/3 non-motor score 475th percentile, or all three non-motor scores 475th percentile) and 146 as ` intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-b (329.0 +/- 96.7 pg/ml, P = 0.006) and amyloid-b/total-tau ratio (8.2 +/- 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits.