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

基本信息

批准号：
10200644
负责人：
Nina Vanessa Kraguljac
金额：
$ 63.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-26 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200644
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 Glutamatergic Agents 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 density drug development extracellular first episode psychosis indexing inflammatory marker multimodality myoinositol neuroimaging neuroinflammation new therapeutic target peripheral blood public health relevance response targeted biomarker white matter white matter change white matter damage

项目摘要

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.

精神分裂症是一种与细微的白质异常相关的复杂疾病随着时间的推移。改变与跨症状维度的疾病严重程度有关，总体较差结果，但没有策略来减弱白质疾病的进展。这主要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贡献因素，但我们不知道疾病早期是否有一段时间影响白质或者如果他们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名未经细化的第一集精神病患者， 60例未经药物的慢性精神病患者和120名匹配的健康对照。我们将使用（1）高级扩散加权成像以测量白质结构完整性，（2）磁共振光谱测量白质中的谷氨酸能和炎症标记，以及（3）血液样本以测量外周炎症和谷氨酸能标记，以检验白质完整性缺陷的假设随着疾病阶段的函数增加，谷氨酸过量和炎症会导致白质病理。确定导致渐进性白质赤字的因素有望改变我们的机械理解并为生物标志物提供针对性药物开发调查的信息谷氨酸能或抗炎剂的潜力延迟或减弱白质的下降精神分裂症。