2/9 - Predictors and Mechanisms of Conversion to Psychosis

2/9 - 转变为精神病的预测因子和机制

• 批准号: 9107918
• 负责人: ELAINE Fran WALKER
• 金额: $ 64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107918
• 关键词: Accounting; Adult; Advisory Committees; Age; American; Antipsychotic Agents; Automobile Driving; Behavioral; Biological; Biological Assay; Biological Markers; Brain; Cells; Clinical; Clinical assessments; Collaborations; Development; Elements; Enrollment; Event-Related Potentials; Frequencies; Goals; Growth; Health; Health Care Costs; Healthcare Systems; Hormones; Hydrocortisone; Immune; Individual; Inflammation; Inflammatory; Ligands; Link; Long-Term Potentiation; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Mental Health; Mental disorders; Methods; Microglia; Modeling; Neurobiology; Neurons; Oxidative Stress; Pathologic Processes; Pathway interactions; Patients; Peripheral; Phase; Physiological; Plasma; Play; Policies; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Preventive Intervention; Process; Productivity; Protocols documentation; Psychotic Disorders; Publications; Ramp; Recruitment Activity; Research; Research Personnel; Rest; Risk; Role; Sampling; Scanning; Schizophrenia; Site; Social Functioning; Societies; Stress; Structure; Symptoms; Synapses; Synaptic plasticity; Syndrome; Testing; Time; Visual; Vulnerable Populations; Water; base; clinical investigation; cognitive function; cost; cytokine; density; follow-up; gray matter; high risk; improved outcome; indexing; inflammatory marker; insight; meetings; neuroinflammation; novel; peripheral blood; programs; research clinical testing; social skills; socioeconomics; symposium; synaptic function; visual plasticity; young adult

 DESCRIPTION (provided by applicant): Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters; these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.

 描述（由适用提供）：精神分裂症和其他精神疾病是严重且使人衰弱的精神疾病，对患者造成了实质性痛苦以及对我们的医疗保健系统的重大挑战。临床高风险（CHR）前代是精神病发作之前的时期，临床症状逐渐出现并功能下降。年轻人中CHR综合征的存在与以后的精神病发展有关的风险增加（约30％）。北美前驱纵向研究（NAPL）和其他CHR研究在预测精神病方面取得了长足的进步，并显示出在CHR转化器中从前心理前的灰质（PFC）灰色物质（GM）密度加速的加速减少，从而在精神病前到精神病发作，但由于无法进行转换的一部分，因此在精神病后开始，不再是一部分的精神，以前是重复进行的。在NAPLS2中，我们发现在精神病预测转化之前，静息状态（RS）丘脑甲状腺皮质功能连通性的破坏并与GM下降速度相关，但我们不知道RS-Dysconnectectivity在前期期间是否渐进。此外，在NAPLS2中，基线促炎性细胞因子的血浆标志物预测转换器中GM损耗的速率；这些相同的标记也与RS-Dysnectectiation相关。我们尚不知道这些炎症标志物是否会驱动大脑结构/功能的变化，还是这些变化的后果。同样，较高水平的皮质醇和较低的不匹配阴性预测精神病和PFC GM下降率，彼此相关，并与RS连接性和细胞因子的量度相关。该应用是对九个位点的纵向研究的竞争性更新，旨在确定临床综合征进展的脑过程，这些临床综合征的发展是精神病前期的特征。目标是：1）确定转基因下降的前轨迹和使用MRI发展精神病的CHR静止状态大脑连接性的破坏，以及2）确定与精神病过渡相关的炎症和可塑性机制。在两年的时间内，该研究将反复衡量这些指标，同时检查大脑功能，社会和认知功能以及症状进展的物理指标的变化。多站点协作将遵循大型CHR（n = 378），并与人口统计学匹配的比较（n = 162）样本，这些样本将对生物学和行为变化进行全面评估。这种方法将回答有关导致精神病的大脑变化起源的重要问题，并将提供有关停止或米蒂加蒂格的可能方法的见解，并促进我们对风险预测的理解，这都是预防的关键步骤。