GDF10与缺血性脑卒中病后认知功能障碍关系的研究

Post-stroke cognitive impairment (PSCI) is common after stroke and its recognition is crucial, as it impacts on rehabilitation. The mechanisms of PSCI have not well clarified. Recently, studies reported that growth differentiation factor 10 (GDF10) could spur on axonal sprouting, growth and functional recovery after stroke through transforming TGFβRI and TGFβRII in vitro and in animal models. Therefore, we assume that GDF10 and TGFβ receptors may be associated with the risk of PSCI. Nevertheless, to date and to our knowledge, there is no such an epidemic study. Our group has finished the project named “the China Antihypertensive Trial in Acute Ischemic Stroke” (CATIS). On this basis, a study will be conducted to explore the associations between serum GDF10, TGFβRI and TGFβRII levels and risk of PSCI, as well as the ability of GDF10 and TGFβ receptors to distinguish patients at high risk of PSCI. Overall, Our study will provide epidemic evidence for the mechanisms of PSCI, and new insights into secondary prevention and therapy for PSCI.

卒中后认知障碍（post-stroke cognitive impairment, PSCI）是脑卒中的常见并发症。它危害较大，亟需对其进行早期筛查诊断，但PSCI的发病机制未完全明确。体外实验和动物模型显示，GDF10(Growth differentiation factor 10)可能通过调控TGFβRI和TGFβRII，进而促进卒中后神经元轴突的萌芽生长以及机体的功能恢复。因此，GDF10及其调控因子缺乏可能是PSCI发生的重要机制，但目前尚无人群研究报道。本研究将选取急性缺血性脑卒中病例（来源于中美合作CATIS项目），检测其基线血清GDF10、TGFβRI和TGFβRII的水平，随访并评价患者认知功能，探讨GDF10和其调控因子水平与PSCI发生的关联，并评估它们对PSCI发病风险的预测价值。本项目将为PSCI的机制研究提供线索，也将为其二级预防以及新药研发提供新靶点和新思路。

背景：生长分化因子15 (Growth differentiation factor 15, GDF-15)是一种应激反应性蛋白，报道称其与死亡和心血管事件独立相关。但GDF-15与卒中预后的研究尚不多见。..方法：采用Quantikine Human GDF-15 ELISA试剂盒（R&D Systems, Inc）对3066位病人的血清GDF-15浓度进行了检测。主要随访结局是3个月内死亡、严重残疾心血管事件和卒中复发。研究还利用Mini-Mental State Examination和Montreal Cognitive Assessment量表对其中的569位病人进行了认知功能评价。采用多因素Logistic回归或Cox比例危险模型评估GDF-15与预后的关联。..结果：随访3个月后，分别有676 (22.05%)、86 (2.80%)、81(2.64%)和51位(1.66%)患者出现严重残疾、死亡、血管事件或卒中复发。在调整了年龄、性别、吸烟、饮酒和基线NIHSS评分后，log10-GDF15每增高1SD，死亡或严重残疾发生风险增加0.26倍(95%CI=0.15-0.39)，严重残疾风险增加0.13倍(95%CI=0.02-0.25)，死亡风险增加0.79倍(95%CI=0.48-1.16)。GDF-15亦能提高对死亡和严重残疾的预测能力（c-statistic, net reclassification index 和 integrated discrimination improvement 等指标显著增高）。同时我们也发现，在进行了认知评价的患者中，388位发生了认知障碍。GDF-15浓度高于1073 ng/L，患者认知障碍风险增高0.76倍（95%CI=0.09-1.40）。..结论：GDF-15浓度升高与AIS患者的不良预后相关，基线血清GDF-15有助于鉴别预后不良的高危AIS患者。