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

谷氨酸过量和炎症对精神病进行性白质变化的影响

• 批准号: 10657727
• 负责人: Nina Vanessa Kraguljac
• 金额: --
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-26 至 2023-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657727
• 关键词: Affect; Anti-Inflammatory Agents; Antipsychotic Agents; Attenuated; Blood specimen; Choline; Chronic; Complex; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Disease Progression; Drug Targeting; Enrollment; Glutamate Metabolism Pathway; Glutamates; Glutamine; Image; Imaging Techniques; Inflammation; Inflammatory; Magnetic Resonance Spectroscopy; Measures; Mental disorders; Modeling; Morphology; Neurites; Outcome; Pathology; Patients; Peripheral; Process; Psychoses; Reporting; Schizophrenia; Severity of illness; Structure; Symptoms; Techniques; Testing; Time; Water; White Matter Disease; comparison control; density; drug development; extracellular; first episode psychosis; indexing; inflammatory marker; multimodal neuroimaging; myoinositol; neuroinflammation; new therapeutic target; peripheral blood; public health relevance; response; targeted biomarker; white matter; white matter change; white matter damage

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.

精神分裂症是一种复杂的疾病，与微妙的白质异常相关，并且会进展 随着时间的推移。改变与跨症状维度的疾病严重程度以及整体更差有关 结果，但不存在减缓白质疾病进展的策略。这很大程度上是因为 潜在的病理生理过程仍然未知。谷氨酸过量和炎症可能是 促成因素，但我们不知道在疾病早期是否有一段时期这些因素会影响白质 或者它们是否会在疾病阶段改变白质。 我们建议使用多模式神经影像学来研究 60 名未接受药物治疗的首发精神病患者， 60 名未接受药物治疗的慢性精神病患者和 120 名匹配的健康对照者。我们将使用（1）高级 扩散加权成像测量白质结构完整性，(2) 磁共振波谱 测量白质中的谷氨酸和炎症标记物，以及 (3) 测量血液样本 外周炎症和谷氨酸标记物以检验白质完整性缺陷的假设 随着疾病阶段的变化而增加，谷氨酸过量和炎症会导致白质 病理。 识别导致进行性白质缺陷的因素有望 改变我们的机制理解并为靶向药物开发研究的生物标志物提供信息 谷氨酸或抗炎药延迟或减轻白质衰退的潜力 精神分裂症。