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: 9303457
• 负责人: Scott W Woods
• 金额: $ 38.15万
• 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/9303457
• 关键词: Adult; Advisory Committees; Age; American; Anatomy; Antipsychotic Agents; Automobile Driving; Behavioral; Biological; Biological Assay; Biological Markers; Brain; Cells; Clinical; Clinical assessments; Collaborations; Development; Disease; Elements; Enrollment; Event-Related Potentials; Frequencies; Goals; Growth; Health Care Costs; Healthcare Systems; Hormones; Hydrocortisone; Immune; Impairment; 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; 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; public health relevance; research clinical testing; social skills; socioeconomics; symposium; synaptic function; 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且使人衰弱的精神疾病，会给患者带来巨大痛苦，并对我们的医疗保健系统造成重大挑战。临床高风险（CHR）前驱期是发病前的时期。当临床症状逐渐出现且功能衰退时，年轻人出现 CHR 综合征与后来发生精神病的哮喘风险（约 30%）相关。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，并显示从精神病发作前到精神病发作后，CHR 转换器的前额皮质 (PFC) 灰质 (GM) 密度加速减少，但机制驱动转换仍然难以捉摸，部分原因是没有研究包括精神病发作前的重复测量。在 NAPLS2 中，我们发现精神病发生前的静息态 (rs) 丘脑皮质功能连接中断可以预测。转化并与 GM 下降率相关，但我们不知道在前驱症状期间 rs 连接断开是否是进展性的。此外，在 NAPLS2 中，基线时促炎细胞因子的血浆标记物预测了这些相同标记物的 GM 损失率。我们还不知道这些炎症标志物是否会导致大脑结构/功能的变化，或者是这些变化的结果。同样，较高水平的皮质醇和较低的失配消极性可以预测精神病和抑郁症。 PFC GM 下降率并相互关联，并与 rs 连接性和细胞因子的测量相关。该应用程序是一项九个站点的纵向研究的竞争性更新，旨在确定临床综合征进展的大脑过程。目标是：1) 使用 MRI 确定发生精神病的 CHR 个体中 GM 下降和静息态大脑连接中断的发病前轨迹，以及 2) 识别相关的炎症和可塑性机制。在两年的时间内，该研究将反复测量这些指标，同时检查大脑功能、社交和认知功能以及症状进展等生理指标的变化。大量 CHR (n= 378) 和人口统计匹配的比较 (n= 162) 样本将经历全面的生物学和行为变化，这种方法将回答有关引起精神病的大脑变化起源的重要问题，并将提供深入了解。可能的方法来停止或减轻病理过程并增进我们对风险预测的理解，这都是预防的关键步骤。