首发精神分裂症细胞因子水平异常与静息态脑功能关系的纵向研究

With the deepening understanding of the relationships between central nervous system and immune system, a number of studies from neurobiochemistry, development, genics, neuroimaging and histology have pointed out that abnormal cytokines closely related with the occurrence of schizophrenia. However, the results were not completely consistent due to the different illness duration, status or drug therapys. Furthermore, there is also a lack of study focusing on the direct relationships between cytokines and brain functions. Resting-state functional magnetic resonance imaging (rs-fMRI) can study the spontaneous functional activity in a resting brain, which is demonstrated to have unique value in studying the pathological mechanism of schizophrenia. Thus, we designed a prospective and longitudinal study to assess dynamic relationship between resting-state brain functions and alterations of a series of cytokines by employing rs-fMRI techniques in drug-naive first-episode schizophrenia patients. Furthermore, we provided an additional anti-inflammatory treatment to evaluate the clinical therapeutic effect and specific changes associated with resting-state brain functions. Through above designs, this study aims to: 1) explore the role of cytokines from serum and cerebrospinal fluid in schizophrenia pathological mechanism and seek the specific cytokines reflecting characteristics and states of schizophrenia, which might provide biological and imaging markers for follow-up screening people at high risk for schizophrenia; 2) explore the mechanism of anti-inflammation therapy on brain function changes in schizophrenia, and provide imaging evidence for the decision-making of clinical anti-inflammatory therapy.

随着对神经与免疫之间关系的认识深入，大量研究从神经生化、发育、基因、组织学和神经影像等角度发现细胞因子与精神分裂症的发生密切相关。但受病程、疾病状态和药物的影响，结果并不完全一致，也缺乏针对细胞因子与脑功能变化关系的直接研究。静息态功能磁共振成像(rs-fMRI)能够无创性研究静息状态脑的自发功能活动，在精神分裂症病理机制的探索上具有独特价值。本课题拟应用rs-fMRI，前瞻性、纵向评价首发未用药精神分裂症患者血清和脑脊液中不同种类、功能的细胞因子与静息态脑功能之间的动态变化关系，并评价与辅助抗炎治疗相关的特异性细胞因子和脑功能改变，旨在：1）探索细胞因子在精神分裂症中的病因和病理学机制，寻找表征精神分裂症和其疾病状态的特异性细胞因子，为精神分裂症高危人群的随访筛查提供生物学和影像学标志物；2）探索辅助抗炎治疗对精神分裂症脑功能改变的作用机制，为临床辅助抗炎治疗的决策提供影像学依据。

精神分裂症是一种常见的高致残性的慢性精神疾病，发生机制至今未明。随着对神经与免疫之间关系的认识深入，大量研究从神经生化、发育、基因、组织学和神经影像等角度发现细胞因子与精神分裂症的发生密切相关。静息态功能磁共振成像(rs-fMRI)能够无创性研究静息状态脑的自发功能活动，在精神分裂症病理机制的探索上具有独特价值。本课题应用rs-fMRI，前瞻性、纵向评价首发精神分裂症患者细胞因子与静息态脑功能之间的动态变化关系，并评价与辅助抗炎治疗相关的特异性细胞因子和脑功能改变，结果发现：1）精神分裂症患者多种促炎因子(IL-1β、IL-4、IL-6和IL-8)水平在基线时显著高于健康对照组，而在辅助抗炎治疗后IL-8水平下降；较高的IL-6水平和较低的IL-8水平预测阴性症状的改善更好；较高的IL-6水平预示着抑郁症状的改善程度较低；较高的干扰素IFN-γ水平预测较低的治疗兴奋性症状；2）炎症因子高表达组较炎症因子低表达组的ALFF值、ReHo值在多个脑区存在显著差异，这些脑区主要涉及额顶叶皮层及部分视觉皮层，提示脑功能连接障碍和炎症相关的脑发育异常可能共同在精神分裂症的发生发展中起作用；3）高级视觉网络和楔前叶网络在精神分裂症和健康对照组存在显著差异，在两个网络中脑功能连接差异主要位于双侧纹状体区，且与IL-1β和阳性症状（包括PANSS P3评分）存在相关性，提示炎症因子可能与精神分裂症急性期的阳性症状特别是幻听存在密切关联；4）基于上述研究成果，进一步应用多参数MRI成像（VBM、DTI及rs-fMRI）补充分析了精神分裂症急性期常见症状幻听可能的神经机制，从结构和功能角度对其发生机制进行了深入探讨。本研究结果从细胞因子角度理解精神分裂症病因和病理学机制提供了新的视角，为精神分裂症高危人群的随访筛查提供了新的方法，也为探索辅助抗炎治疗对精神分裂症的治疗提供了新的思路。