TGF-β1 与首发精神分裂症认知功能缺陷和大脑皮质厚度减少有关。
TGF-β1 is associated with deficits in cognition and cerebral cortical thickness in first-episode schizophrenia.
机构信息
From the Peking University Huilongguan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China (Pan, Zhou, Tong, Li, Huang, Feng, Chen, Yang, S. Tan, Wang, B. Tian, Y. Tan, L. Tian); the Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, Estonia (Yan, Xuan, L. Tian); the Department of Pharmacy, Peking University First Hospital, Beijing, China (Cui); and the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, USA (Hong).
From the Peking University Huilongguan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China (Pan, Zhou, Tong, Li, Huang, Feng, Chen, Yang, S. Tan, Wang, B. Tian, Y. Tan, L. Tian); the Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, Estonia (Yan, Xuan, L. Tian); the Department of Pharmacy, Peking University First Hospital, Beijing, China (Cui); and the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, USA (Hong)
出版信息
J Psychiatry Neurosci. 2022 Mar 17;47(2):E86-E98. doi: 10.1503/jpn.210121. Print 2022 Mar-Apr.
BACKGROUND
Evidence indicates that cytokines are associated with cognitive deficits in schizophrenia; however, the underlying brain-behaviour mechanisms remain unclear. We hypothesized that aberrations in brain structural connectivity mediate the cytokine effect in schizophrenia.
METHODS
In this study, we recruited patients with first-episode schizophrenia ( = 75, average illness duration 12.3 months, average medication period 0.6 days) and healthy controls ( = 44) of both sexes. We first conducted whole-blood RNA sequencing to detect differentially expressed genes. We also explored transcriptomic data on the dorsal lateral prefrontal cortices (dlPFC) retrieved from the CommonMind Consortium for gene functional clustering; we measured plasma transforming growth factor β1 (TGF-β1) levels by enzyme-linked immunosorbent assay; we acquired high-resolution -weighted MRI data on cortical thickness MRI; and we assessed cognitive function using the validated Chinese version of the MATRICS Consensus Cognitive Battery. We compared these parameters in patients with schizophrenia and controls, and analyzed their associations.
RESULTS
Patients with schizophrenia had higher TGF-β1 at both the mRNA level (log fold change = 0.24; adjusted = 0.026) and the protein level (12.85 ± 6.01 μg/mL v. 8.46 ± 5.15 μg/mL, adjusted < 0.001) compared to controls. Genes coexpressed with in the dlPFC were less abundant in patients with schizophrenia compared to healthy controls. In patients with schizophrenia, TGF-β1 protein levels were inversely correlated with cortical thickness, especially of the lateral occipital cortex ( = -0.47, adjusted = 0.001), and with the MATRICS Consensus Cognitive Battery visual learning and memory domain ( = -0.50, adjusted < 0.001). We found a complete mediation effect of the thickness of the lateral occipital cortex on the negative relationship between TGF-β1 and visual cognition ( < 0.05).
LIMITATIONS
We did not explore the effect of other blood cytokines on neurocognitive performance and cortical thickness. Participants from the CommonMind Consortium did not all have first-episode schizophrenia and they were not all antipsychotic-naive, so we could not exclude an effect of antipsychotics on TGF-β1 signalling in the dlPFC. The sample size and cross-sectional design of our study were additional limitations.
CONCLUSION
These findings highlighted an association between upregulated blood levels of TGF-β1 and impairments in brain structure and function in schizophrenia.
背景
有证据表明细胞因子与精神分裂症认知缺陷有关；然而，潜在的脑-行为机制尚不清楚。我们假设大脑结构连接的异常会介导精神分裂症中的细胞因子效应。
方法
本研究纳入了 75 例首发精神分裂症患者（平均发病时间 12.3 个月，平均用药时间 0.6 天）和 44 例健康对照者（男女不限）。我们首先进行全血 RNA 测序以检测差异表达基因。我们还探索了从 CommonMind 联合会获取的背外侧前额叶皮质（dlPFC）的转录组数据，以进行基因功能聚类；我们通过酶联免疫吸附测定法测量血浆转化生长因子β1（TGF-β1）水平；我们获取皮质厚度 MRI 的高分辨率 T1 加权 MRI 数据；并使用经过验证的中文版 MATRICS 共识认知电池评估认知功能。我们比较了精神分裂症患者和对照组的这些参数，并分析了它们的相关性。
结果
与对照组相比，精神分裂症患者的 TGF-β1 在 mRNA 水平（log 倍数变化=0.24；调整后 P=0.026）和蛋白水平（12.85±6.01μg/ml 比 8.46±5.15μg/ml，调整后 P<0.001）均升高。与 共表达的 dlPFC 基因在精神分裂症患者中比健康对照组更丰富。在精神分裂症患者中，TGF-β1 蛋白水平与皮质厚度呈负相关，尤其是外侧枕叶皮质（r=-0.47，调整后 P=0.001），与 MATRICS 共识认知电池的视觉学习和记忆域（r=-0.50，调整后 P<0.001）呈负相关。我们发现外侧枕叶皮质厚度对 TGF-β1 与视觉认知之间负相关关系的完全中介作用（P<0.05）。
局限性
我们没有探讨其他血液细胞因子对神经认知表现和皮质厚度的影响。来自 CommonMind 联合会的参与者并非全部患有首发精神分裂症，也并非全部未使用抗精神病药物，因此我们不能排除抗精神病药物对 dlPFC 中 TGF-β1 信号的影响。我们研究的样本量和横断面设计是另外的局限性。
结论
这些发现强调了精神分裂症中血液 TGF-β1 水平升高与大脑结构和功能损伤之间的关联。
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