MRI Anatomy of Schizophrenia

描述（由申请人提供）： 背景资料：多年来，精神分裂症这种严重的精神疾病被认为是青少年大脑发育过程中出现的发育异常的结果，但其大脑异常在发病后没有改变。然而，现在，一个新的模式，发病后进展的损失，脑灰质和脑液空间（CSF）的结构MRI扫描可见的增加已成为精神分裂症研究的热点。与其他研究一样，我们目前的Merit奖赞助的纵向MRI研究及其68篇出版物提供了强有力的进展初步证据。然而，许多问题仍然存在。并非所有的研究者都同意灰质损失的进展是精神分裂症的一部分，治疗药物在进行性大脑变化中的作用也存在争议。 研究方法：为了回答关于进展的关键问题，我们提出了一项为期5年的纵向自然主义研究，分为两组，即首发精神分裂症（FESZ）和慢性精神分裂症（CSZ），均与年龄、性别和父母社会经济地位匹配的相同数量的健康对照（HC）进行比较，这些健康对照将具有相同的纵向方案;所有受试者都将进行3 T MRI扫描。FESZ将进行MRI和临床/诊断评价：1）发作时，客观定义为首次住院（5年内共N=110）; 2）初始扫描后6个月（共N=63）; 3）初始扫描后12个月（共N=40）; 4）初始扫描后30个月（共N=20）。每个时间点的FESZ受试者数量反映了我们记录的随访返回率和5年研究的持续时间限制，并基于每年进入研究的22例新FESZ。我们将使用MRI扫描的手动感兴趣区域分析以及临床症状/体征测量的金标准来回答关键问题。为了便于比较，FESZ和CSZ将接受相同的初始和随访临床和神经心理学评价。治疗医生将每月跟踪用药状态，并跟踪依从性、剂量和负荷与MRI/临床变化的相关性。这项自然主义研究的一个重要特征是，基于初步数据的功效计算表明，FESZ样本N将足够大，可以根据药物、性别和其他变量进行分组。我们将使用三种发作指标，即精神分裂症发作量表、药物发作和首次住院，并将根据MRI变化的预测值确定哪一种提供了最佳的发作指标。 假设：我们假设，根据初步数据，发病后进展最快的FESZ在发病后的前6个月，相比之下，28 CSZ在初始和30个月的随访。在FESZ中，我们预期在广泛的新皮层区域中的灰质进行性丢失，在额叶和颞叶中最强烈，并且在这些叶中，在与SZ功能异常相关的特定脑区域中最强烈和快速，例如在上级颞回语言和听觉处理区域中，在那里它将与组织混乱和思维障碍的临床症状的进展相关。我们预计抗精神病药物可以减缓灰质损失和临床症状的进展，而情绪稳定剂可以减缓灰质进展，但对临床症状的影响较小。 公共卫生相关性： 重要性：我们的初步发现，FESZ的MRI变化在发病后迅速进展，如果被拟议的研究证实，将改变我们对这种疾病的概念，并建议在疾病发作时进行密集的药理学和心理社会干预试验。此外，我们的研究将有助于确定哪些药物治疗可以防止疾病进展。除了对我们对精神分裂症进行性脑病理学的理解进行潜在的重新表述之外，这项工作还将增加我们对精神分裂症影响大脑哪些区域的知识，这本身就是一个重要的贡献。与退伍军人健康相关：精神分裂症影响1%的总人口，是VA痛苦，发病率和费用的主要来源之一。事实上，每年治疗的10万名精神分裂症患者占VA医疗费用的近12%。增加对精神分裂症潜在大脑区域的了解将改善对受折磨退伍军人的治疗和护理。

DESCRIPTION (provided by applicant): Background: For many years the serious mental illness of schizophrenia was thought of as the consequence of abnormalities in development which emerged in the course of adolescent brain development, but whose brain abnormalities did not change after onset. Now, however a new paradigm of post-onset progression of loss of brain gray matter and concomitant increase of brain fluid spaces (CSF) visible on structural MRI scans has become a hot topic in schizophrenia research. As well as other studies, our current Merit award-sponsored longitudinal MRI study and its 68 publications provide strong preliminary evidence of progression. Still, many questions remain. Not all investigators agree on progression of gray matter loss as a part of schizophrenia, and the role of treatment medication in progressive brain changes is controversial. Research Methods: To answer key questions about progression, we propose a 5 year longitudinal naturalistic study in two groups, first episode schizophrenia (FESZ) and chronic schizophrenia (CSZ), both compared with equal numbers of healthy controls (HC) matched on age, gender and parental socio- economic status who will have the same longitudinal protocol; all subjects will have 3T MRI scans. FESZ will have MRIs and clinical/diagnostic evaluations: at 1) onset, objectively defined as first hospitalization (N=110 total over 5 years); 2) 6 months after initial scan (N=63 total); 3) 12 months after initial scan (N=40 total); and 4) 30 months after initial scan (N=20 total). The FESZ subject numbers at each time point reflect both our documented follow-up return rate and the duration constraints of a 5 year study and are based on 22 new FESZ entering each year of the study. We will use the gold standard of manual Region of Interest analysis of MRI scans together with clinical symptom/sign measures to provide answers to key questions. To facilitate comparison FESZ and CSZ will receive the same initial and follow-up clinical and neuropsychological evaluations. Medication status will be tracked monthly by the treating physician and compliance, dosage and load will be tracked for association with MRI/clinical changes. An important feature of this naturalistic study is that power calculations based on preliminary data indicate the FESZ sample N will be large enough to permit subgrouping on the basis of medication, gender and other variables. We will use three measures of onset, the schizophrenia onset scale, medication onset and first hospitalization and will determine which provides the best measure of onset, based on predictive value for MRI changes. Hypotheses: We hypothesize, based on preliminary data, that post-onset progression is most rapid in FESZ in the first 6 months after onset, compared with 28 CSZ at initial and at 30 month follow-up. In FESZ we expect gray matter progressive loss in widespread neocortical areas, most intense in frontal and temporal lobe, and, within these lobes, most intense and rapid in particular brain regions linked to SZ functional abnormalities, such as, for example, in superior temporal gyrus language and auditory processing regions, where it will be associated with progression of clinical symptoms of disorganization and thought disorder. We expect antipsychotic medication to slow progression of both gray matter loss & clinical symptoms while mood stabilizers will slow gray matter progression but will have lesser effect on clinical symptoms. PUBLIC HEALTH RELEVANCE: Significance: Our preliminary findings of a rapid post-onset progression of MRI changes in FESZ, if confirmed by the proposed study, would alter our conceptualization of the disorder, and suggest the need for intensive pharmacologic and psychosocial intervention trials at disease onset. Moreover, our study will help define which pharmacological treatments protect against progression. In addition to this potential reformulation of our understanding of progressive brain pathology in schizophrenia, the work proposed will increase our knowledge about what areas of the brain are affected in schizophrenia, an important contribution in its own right. Relevance to Veterans Health: Schizophrenia affects 1% of the general population and is one of the major sources of suffering, morbidity and expense in the VA. In fact, the 100,000 patients treated with schizophrenia each year account for nearly 12% of VA healthcare costs. Increase in knowledge about the brain areas underlying schizophrenia will lead to improvement in treatment and care for afflicted veterans.