VISN22 Mental Illness Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA.
Imaging Research Center, University of California, Davis, 4701 X Street, Sacramento, CA 95817, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Davis, 2230 Stockton Blvd, Sacramento, CA 95817, USA.
Neuroimage Clin. 2023;39:103461. doi: 10.1016/j.nicl.2023.103461. Epub 2023 Jun 27.
Brain metabolite abnormalities measured with magnetic resonance spectroscopy (MRS) provide insight into pathological processes in schizophrenia. Prior meta-analyses have not yet answered important questions about the influence of clinical and technical factors on neurometabolite abnormalities and brain region differences. To address these gaps, we performed an updated meta-analysis of N-acetylaspartate (NAA), choline, and creatine levels in patients with schizophrenia and assessed the moderating effects of medication status, echo time, measurement quality, and other factors.
We searched citations from three earlier meta-analyses and the PubMed database after the most recent meta-analysis to identify studies for screening. In total, 113 publications reporting 366 regional metabolite datasets met our inclusion criteria and reported findings in medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex, frontal white matter, hippocampus, thalamus, and basal ganglia from a total of 4445 patient and 3944 control observations.
Patients with schizophrenia had reduced NAA in five of the six brain regions, with a statistically significant sparing of the basal ganglia. Patients had elevated choline in the basal ganglia and both prefrontal cortical regions. Patient creatine levels were normal in all six regions. In some regions, the NAA and choline differences were greater in studies enrolling predominantly medicated patients compared to studies enrolling predominantly unmedicated patients. Patient NAA levels were more reduced in hippocampus and frontal white matter in studies using longer echo times than those using shorter echo times. MPFC choline and NAA abnormalities were greater in studies reporting better metabolite measurement quality.
Choline is elevated in the basal ganglia and prefrontal cortical regions, suggesting regionally increased membrane turnover or glial activation in schizophrenia. The basal ganglia are significantly spared from the well-established widespread reduction of NAA in schizophrenia suggesting a regional difference in disease-associated factors affecting NAA. The echo time findings agree with prior reports and suggest microstructural changes cause faster NAA T2 relaxation in hippocampus and frontal white matter in schizophrenia. Separating the effects of medication status and illness chronicity on NAA and choline abnormalities will require further patient-level studies. Metabolite measurement quality was shown to be a critical factor in MRS studies of schizophrenia.
磁共振波谱（MRS）测量的脑代谢物异常为精神分裂症的病理过程提供了深入了解。先前的荟萃分析尚未回答关于临床和技术因素对神经代谢物异常和脑区差异影响的重要问题。为了解决这些差距，我们对精神分裂症患者的 N-乙酰天门冬氨酸（NAA）、胆碱和肌酸水平进行了更新的荟萃分析，并评估了药物状态、回波时间、测量质量和其他因素的调节作用。
我们在最近的荟萃分析后，从三个先前的荟萃分析的参考文献和 PubMed 数据库中搜索引文，以筛选研究。共有 113 篇发表的论文报告了 366 个区域性代谢物数据集，符合我们的纳入标准，并报告了来自总共 4445 名患者和 3944 名对照观察的内侧前额叶皮层（MPFC）、背外侧前额叶皮层、额叶白质、海马、丘脑和基底节的发现。
精神分裂症患者在六个脑区中有五个脑区的 NAA 降低，基底节区的 NAA 明显保留。患者的基底节区和两个前额皮质区的胆碱升高。所有六个区域的患者肌酸水平正常。在一些区域，与招募主要未用药患者的研究相比，招募主要用药患者的研究中 NAA 和胆碱的差异更大。与使用较短回波时间的研究相比，使用较长回波时间的研究中患者的 NAA 水平在海马体和额叶白质中降低更明显。报告代谢物测量质量更好的研究中，MPFC 胆碱和 NAA 异常更大。
胆碱在基底节区和前额皮质区升高，提示精神分裂症中膜周转率或胶质激活增加。基底节区明显免受精神分裂症中广泛的 NAA 降低的影响，这表明影响 NAA 的疾病相关因素存在区域性差异。回波时间的发现与先前的报告一致，并表明微结构变化导致精神分裂症中 NAA 在海马体和额叶白质中的 T2 弛豫更快。进一步的患者水平研究将需要分离药物状态和疾病慢性对 NAA 和胆碱异常的影响。代谢物测量质量是精神分裂症 MRS 研究中的一个关键因素。
