Supplementary Material for: Sterol Regulatory Element Binding Transcription Factor-1 Gene Variation and Medication Load Influence White Matter Structure in Schizophrenia

Background: Diffusion tensor imaging (DTI) studies have shown a widespread disruption of white matter (WM) microstructure in schizophrenia. Furthermore, higher fractional anisotropy (FA) has been consistently correlated with the severity of psychotic symptoms. Antipsychotic drugs (APDs) affect lipid homeostasis. Gene polymorphisms in sterol regulatory element binding transcription factor (SREBF)-1 and SREBF-2 have been associated with schizophrenia. Methods: In a sample of 65 patients affected by chronic schizophrenia, we investigated the effect of ongoing APD medication, SREBF-1 rs11868035 polymorphism and SREBF-2 rs1052717 polymorphism on the WM microstructure, using tract-based spatial statistics with threshold-free cluster enhancement. Results: We reported increased FA associated with the risk rs11868035 G/G genotype in several WM tracts, mainly located in the left hemisphere, and opposite effects of the APD medication load, with reduced FA and generally increased diffusivity. These opposite effects overlapped in the forceps minor, cingulum, uncinate fasciculus, the superior and inferior longitudinal fasciculi, the corticospinal tract, inferior fronto-occipital fasciculus and the anterior thalamic radiation. Conclusion: We suggest that changes of WM structure could be an as yet poorly explored biomarker of the effects of APDs, to be further investigated in prospective studies correlating long-term clinical effects with changes of DTI measures in specific WM tracts contributing to the functional integrity of the brain.背景：扩散张量成像（diffusion tensor imaging, DTI）研究显示，精神分裂症患者存在广泛的白质（white matter, WM）微结构损伤。此外，更高的各向异性分数（fractional anisotropy, FA）始终与精神病性症状的严重程度呈正相关。抗精神病药物（antipsychotic drugs, APDs）可影响脂质稳态；固醇调节元件结合转录因子（sterol regulatory element binding transcription factor, SREBF）-1与SREBF-2的基因多态性已被证实与精神分裂症相关。 方法：本研究纳入65例慢性精神分裂症患者，采用结合无阈值聚类增强的基于束的空间统计方法（tract-based spatial statistics with threshold-free cluster enhancement），探究当前抗精神病药物治疗剂量、SREBF-1 rs11868035基因多态性及SREBF-2 rs1052717基因多态性对白质微结构的影响。 结果：本研究发现，多个主要位于左侧半球的白质束中，风险型rs11868035 G/G基因型与更高的FA值相关；而抗精神病药物治疗剂量则表现出相反的效应，即FA值降低且弥散系数普遍升高。这两种相反的效应在小钳束、扣带束、钩状束、上纵束、下纵束、皮质脊髓束、额枕下束及丘脑前辐射中存在重叠。 结论：本研究提示，白质结构改变可能是抗精神病药物效应的一种尚未被充分探索的生物标志物，未来可开展前瞻性研究，将长期临床疗效与维持脑功能完整性的特定白质束的DTI指标变化相关联，以进一步开展相关验证工作。