MR Brain Diffusion Tensor Imaging in Schizophrenia

 描述（由申请人提供）： 这项申请是4年资助的竞争性续期，延长了在前一个赠款期内进行的早期工作。在这个应用程序中，我们将提高我们的理解精神分裂症的白色物质的变化，通过引入新的工具和方法，更具体的基础病理学。这项工作是高度相关的整体VA使命，精神分裂症患者利用40%的VA医疗资源。从历史上看，白色物质在精神分裂症中的作用在很大程度上被忽视了，大多数生物学假设都集中在灰质的异常上。尽管精神分裂症现在被认为是一种连接障碍综合症，而且是白色物质提供了神经元之间的长距离通信。直到最近，随着弥散磁共振成像（dMRI）的引入，注意力才慢慢转移到精神分裂症白色物质的研究上。尽管如此，迄今为止的发现尚未导致对病因学的理解或新的药物治疗，主要是因为dMRI测量对潜在的显微结构病理学是非特异性的。然而，新的方法在病理学方面更具体，并且基于我们使用来自dMRI的游离水和磁共振波谱（MRS）的初步数据，我们假设精神分裂症中的白色物质受到至少两种不同病理过程的损害，所述病理过程发生在疾病的不同阶段，即，神经炎症和神经变性。在这里，我们将使用新的工具和方法，以确定精神分裂症的白色物质的特定变化的神经生物学性质，时间过程和功能后果。具体来说，我们将使用几个最近开发的MRI采集和分析方法，并将其应用于早发性精神分裂症和慢性精神分裂症人群，以及匹配的健康对照。根据生物学假设，我们预测：A）早发性精神分裂症可能与病理学有关（神经炎症）影响使用神经炎症的dMRI和磁共振波谱学指标观察到的细胞外体积; B）慢性精神分裂症可能与增加的细胞病理学相关（神经变性），使用dMRI和MRS测量观察;和C）神经炎症和神经变性两者都对轴突传导传递速度有影响，使用半球间转移任务证明，并且这些变化的定位将预测临床特征。一年后还将评估早期精神病患者的纵向变化，以确定在此期间白色物质的进行性变化。精神分裂症的dMRI，MRS和EEG方法的调查将导致精神分裂症的白色物质异常的新发现，包括有关神经炎症和神经退行性过程在疾病的不同阶段发生的作用的新信息，这反过来又将提供一个新的视角，可能涉及抗炎药的早期治疗干预。

 DESCRIPTION (provided by applicant): This application is a competitive renewal for 4 years of funding which extends earlier work conducted during the previous grant period. In this application we will enhance our understanding of the neurobiology of white matter changes in schizophrenia by introducing novel tools and methods that are more specific with respect to underlying pathology. This work is highly relevant to the overall VA mission, as patients with schizophrenia utilize 40% of the VA healthcare resources. Historically, the role of white matter in schizophrenia has been largely overlooked, with the majority of biological hypotheses focused on abnormalities in gray matter. This is despite the fact that schizophrenia is now viewed as a dys-connection syndrome, and that it is white matter that provides long-range communication among neurons. Only recently, with the introduction of diffusion MRI (dMRI), has attention slowly shifted to investigating the roe of white matter in schizophrenia. Nonetheless, findings to date have not led to an understanding of the etiology or to new pharmacological treatment(s), primarily because dMRI measures are nonspecific to underlying microstructural pathology. New methods, however, are more specific with respect to pathology, and based on our preliminary data using free-water derived from dMRI, and magnetic resonance spectroscopy (MRS), we hypothesize that white matter in schizophrenia is compromised by at least two distinct pathological processes that occur at different stages of the disease, i.e., neuroinflammation and neurodegeneration. Here we will use novel tools and methods to identify the neurobiological nature, time course, and functional consequences of specific changes in white matter in schizophrenia. Specifically, we will use several recently developed MRI acquisition and analysis methods, and apply them to both early onset schizophrenia and chronic schizophrenia populations, as well as to matched healthy controls. In terms of biological hypotheses, we predict that: A) early onset schizophrenia is likel associated with pathology (neuroinflammation) affecting extracellular volume observed using dMRI and magnetic resonance spectroscopy indicators of neuroinflammation; B) chronic schizophrenia is likely associated with increasing cellular pathology (neurodegeneration), observed using dMRI and MRS measures; and, C) both neuroinflammation and neurodegeneration have an effect on axonal conduction transmission speed, evinced using an interhemispheric transfer task, and localization of these changes will predict clinical profile. Longitudinal changes will also be evaluated one year later in the early psychosis patients in order to determine progressive changes in white matter over this time period. The investigation of dMRI, MRS, and EEG methods in schizophrenia will lead to novel findings of white matter abnormalities in schizophrenia, including new information about the role of neuroinflammation and neurodegenerative processes that occur at different stages of the disorder, which, in turn, will provide a new perspective on possible treatment interventions that will likely involve anti-inflammatory agents early in the course of illness.