MR Brain Diffusion Tensor Imaging in Schizophrenia

 描述(由申请人提供)： 这项申请是对四年资助的竞争性续期，是对上一批赠款期间开展的早期工作的延伸。在这项应用中，我们将通过引入新的工具和方法来加强我们对精神分裂症白质变化的神经生物学的理解，这些工具和方法在潜在的病理方面更加具体。这项工作与退伍军人管理局的整体任务高度相关，因为精神分裂症患者利用了退伍军人管理局40%的医疗资源。从历史上看，白质在精神分裂症中的作用在很大程度上被忽视了，大多数生物学假说都集中在灰质的异常上。尽管精神分裂症现在被视为一种连接障碍综合征，而且是白质在神经元之间提供远程通信，但这一事实仍然存在。直到最近，随着扩散磁共振成像(DMRI)的引入，人们的注意力才慢慢转移到研究精神分裂症患者脑白质的ROE上。然而，到目前为止，这些发现还没有导致对病因的理解或新的药物治疗(S)，主要是因为dMRI测量对于潜在的微结构病理是非特异性的。然而，新的方法在病理学方面更具特异性，根据我们使用来自dMRI的自由水和磁共振波谱(MRS)的初步数据，我们假设精神分裂症的白质至少受到两个不同的病理过程的影响，这两个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来确定精神分裂症患者脑白质特定变化的神经生物学性质、时间进程和功能后果。具体地说，我们将使用几种最近开发的MRI获取和分析方法，并将它们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组。在生物学假说方面，我们预测：A)早发性精神分裂症可能与影响细胞外体积的病理(神经炎症)有关，使用dMRI和磁共振波谱指标观察神经炎症；B)慢性精神分裂症可能与增加细胞病理(神经变性)有关，使用dMRI和MRS测量；以及C)神经炎症和神经变性都影响轴突传导速度，通过大脑半球间转移任务表现出来，这些变化的定位将预测临床特征。还将在一年后评估早期精神病患者的纵向变化，以确定这段时间内脑白质的进行性变化。对精神分裂症的dMRI、MRS和EEG方法的研究将导致精神分裂症白质异常的新发现，包括关于神经炎症和神经退行性变过程在疾病不同阶段发生的作用的新信息，这反过来将为可能的治疗干预提供新的视角，这些干预可能在病程的早期使用抗炎药。

 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.