Contribution of Glutamate Excess and Inflammation to Progressive White Matter Changes in Psychosis

精神分裂症是一种复杂的疾病，与进展中的细微白质异常有关。 随着时间的推移。改变与所有症状维度的疾病严重程度相关，总体上更糟 结果，但没有战略存在，以减缓白质疾病的进展。这主要是因为 潜在的病理生理过程仍不清楚。谷氨酸过量和炎症可能是 致病因素，但我们不知道在疾病的早期是否有一段时间这些因素会影响白质 或者他们是否改变了疾病阶段的脑白质。 我们建议使用多模式神经成像来研究60名未服药的首发精神病患者， 60例未服药的慢性精神病患者和120例匹配的健康对照组。我们将使用(1)高级 扩散加权成像测量脑白质结构完整性，(2)磁共振波谱 检测脑白质中的谷氨酸和炎症标志物，以及(3)血样检测 外周炎症和谷氨酸能标记物用于检验脑白质完整性缺陷的假说 作为疾病阶段函数而增加，谷氨酸过量和炎症有助于脑白质 病理学。 确定导致进行性白质缺陷的因素有望 转变我们的机械性认识，为靶向药物开发调查提供生物标志物 谷氨酸能或抗炎药延缓或减轻脑白质衰退的可能性 精神分裂症。

Schizophrenia is a complex disorder associated with subtle white matter abnormalities that progress over time. Alterations are associated with disease severity across symptom dimensions and worse overall outcomes, but no strategies exist to attenuate white matter disease progression. This is largely because the underlying pathophysiological processes remain unknown. Glutamate excess and inflammation may be contributing factors, but we do not know if there is a period early in the illness where these affect white matter or if they alter white matter across illness stages. We propose to use multimodal neuroimaging to study 60 unmedicated first-episode psychosis patients, 60 unmedicated chronic psychosis patients, and 120 matched healthy controls. We will use (1) advanced diffusion weighted imaging to measure white matter structural integrity, (2) Magnetic Resonance Spectroscopy to measure glutamatergic and inflammatory markers in white matter, and (3) blood samples to measure peripheral inflammatory and glutamatergic markers to test the hypothesis that white matter integrity deficits increase as a function of illness stage and that glutamate excess and inflammation contribute to white matter pathology. Identification of factors that contribute to progressive white matter deficits holds the promise to transform our mechanistic understanding and inform biomarkers for targeted drug development investigating the potential of glutamatergic or anti-inflammatory agents delaying or attenuating white matter decline in schizophrenia.