Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia 19104, USA.
JAMA Neurol. 2013 Jul;70(7):852-8. doi: 10.1001/jamaneurol.2013.1274.
Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD).
To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression.
Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups.
The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA-associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing.
Biochemical profiling was available for all 20 GBA-associated PD cases, as well as a subset (87 of 242) of the GBA-negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations.
Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) and were more likely to demonstrate cognitive dysfunction (P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 (P = .001), monocyte chemotactic protein 1 (P = .008), and macrophage inflammatory protein 1α (P = .005). The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separate cohort of patients having PD with vs without GBA mutations.
Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.
GBA（mut/wt）携带者中存在的生化异常可能为帕金森病（PD）提供新的发病机制见解和潜在的治疗靶点。
确定患有 PD 且携带 GBA 突变与不携带 GBA 突变的患者在临床表型或血浆蛋白表达方面是否存在差异。
对患有 PD 且携带 GBA 突变与不携带 GBA 突变的患者进行病例对照研究。比较两组之间的临床特征，并对 40 种血浆蛋白进行生化谱分析，以确定两组之间表达不同的蛋白。
发现队列包括 20 名患有 GBA 相关 PD 的患者。将 GBA 相关 PD 病例的临床特征与通过全基因测序排除 GBA 突变的 242 名 PD 患者进行比较。
所有 20 名 GBA 相关 PD 病例以及 GBA 阴性 PD 病例的亚组（242 名中的 87 名）均可进行生化谱分析。复制队列包括 19 名患有 GBA 相关 PD 的患者和 41 名患有 PD 且不携带 GBA 突变的患者。
与不携带 GBA 突变的 PD 患者相比，携带 GBA 突变的 PD 患者的疾病发病年龄更小（P=0.04），且更有可能出现认知功能障碍（P=0.001）。在包括年龄、性别和测定批次作为协变量的多元回归模型中，GBA 突变状态与白细胞介素 8（P=0.001）、单核细胞趋化蛋白 1（P=0.008）和巨噬细胞炎症蛋白 1α（P=0.005）的血浆水平显著相关。在另一组患有 GBA 相关 PD 且不携带 GBA 突变的患者中，白细胞介素 8 与 GBA 突变状态之间的关联得到复制（P=0.03）。
携带 GBA 突变的 PD 患者发病年龄更早，且更有可能出现认知功能障碍。单核细胞相关炎症介质可能在携带 GBA 突变的 PD 患者中升高。
