8/9 Predictors and Mechanisms of Conversion to Psychosis

8/9 转变为精神病的预测因素和机制

• 批准号: 8934147
• 负责人: Scott W Woods
• 金额: $ 55.81万
• 依托单位: YALE 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/8934147
• 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(申请人提供)：精神分裂症和其他精神障碍是严重的和衰弱的精神疾病，给患者带来巨大的痛苦，并对我们的医疗保健系统构成重大挑战。临床高危(CHR)前驱期是精神病发作前的一段时间，此时临床症状逐渐显现，功能下降。在年轻人中出现CHR综合征与高风险(约30%)的精神疾病的未来发展有关。北美前驱纵向研究(NAPLS)和其他CHR研究在预测精神病方面取得了实质性进展，并显示CHR转换者从精神病发作前到精神病后前额叶皮质(PFC)灰质(GM)密度加速下降，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病前的重复测量。在NAPLS2中，我们发现精神错乱前静息状态(Rs)丘脑-皮质功能连接的紊乱可以预测转换，并与GM下降的速度相关，但我们不知道在前驱症状期间RS-连接异常是否进展。此外，在NAPLS2中，基线时促炎细胞因子的血浆标记物预测转换者的GM丢失率；这些相同的标记物也与RS-连通性障碍相关。我们还不知道这些炎性标志物是导致大脑结构/功能变化的原因，还是这些变化的后果。类似地，较高的皮质醇水平和较低的失配负性预测精神病和PFC GM的比率下降，并且彼此相关，与RS连接性和细胞因子的测量相关。这项应用是一项九点纵向研究的竞争性更新，旨在确定以精神病前驱症状为特征的临床症状进展背后的脑过程。我们的目标是：1)利用核磁共振技术确定患有精神病的慢性阻塞性肺病患者中GM下降和静息状态脑连接中断的发病前轨迹，以及2)确定与向精神病过渡相关的炎症和可塑性机制。在两年的时间里，这项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。多地点合作将遵循大的CHR(n=378)和人口统计匹配的比较(n=162)样本，这些样本将接受生物和行为变化的全面评估。这种方法将回答有关导致精神病的大脑变化的起源的重要问题，并将为阻止或减轻病理过程的可能方法提供见解，并提高我们对风险预测的理解，这两个步骤都是预防的关键步骤。