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: 8934145
• 负责人: ELAINE Fran WALKER
• 金额: $ 59.39万
• 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/8934145
• 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; Intervention; Ligands; Link; Long-Term Potentiation; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Mental Health; Mental disorders; Methods; Microglia; Modeling; Neurobiology; Neurons; Outcome; 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; 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（由申请人提供）：精神分裂症和其他精神障碍是严重和衰弱的精神疾病，给患者带来巨大痛苦，对我们的医疗保健系统构成重大挑战。临床高危前驱期是指精神病发作前临床症状逐渐出现和功能下降的时期。在年轻人中出现精神病综合征与后期发展为精神病的风险增加（约30%）相关。北美前驱症状纵向研究（NAPLS）和其他研究在预测精神病方面取得了实质性进展，并显示从精神病发作前到后，前额叶皮层（PFC）灰质（GM）密度在精神病转换器中加速减少，但驱动转换的机制仍然难以捉摸，部分原因是没有研究包括精神病发作前的重复测量。在NAPLS 2中，我们发现精神病之前的静息态（rs）丘脑-皮质功能连接中断可预测转换，并与GM下降速率相关，但我们不知道rs-连接障碍是否在前驱症状期间进行性。此外，在NAPLS 2中，基线时促炎细胞因子的血浆标志物预测了转换器中GM损失的速率;这些相同的标志物也与rs-连接障碍相关。我们还不知道这些炎症标记物是否驱动大脑结构/功能的变化，或者是这些变化的后果。同样，较高水平的皮质醇，和较低的失配负预测精神病和PFC GM下降的速度，并相互关联，并与rs-连接和细胞因子的措施。 该申请是一项9个研究中心的纵向研究的竞争性更新，旨在确定表征精神病前驱症状的临床综合征进展的脑过程。目标是：1）确定发病前的轨迹GM下降和中断休息状态的大脑连接在精神病患者使用MRI，和2）确定炎症和可塑性机制与过渡到精神病。在为期两年的时间里，该研究将反复测量这些指标，同时检查大脑功能，社会和认知功能以及症状进展的生理指标的变化。多中心合作将遵循大样本（n= 378）和人口统计学匹配的比较（n= 162）样本，这些样本将进行生物学和行为变化的全面评估。这种方法将回答有关引起精神病的大脑变化的起源的重要问题，并将提供有关停止或减轻病理过程的可能方法的见解，并促进我们对风险预测的理解，这两个预防的关键步骤。