Imaging White Matter Maturation and Genetic High Risk for Schizophrenia

白质成熟成像和精神分裂症的遗传高风险

• 批准号: 9331746
• 负责人: AMANDA ELLIS LYALL
• 金额: $ 8.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331746
• 关键词: 2 year old; Adult; Affect; Age; Architecture; Belief; Bilateral; Biological; Biological Markers; Boston; Brain; Cerebrum; Child; Childhood; Clinical; Cognitive; Collection; Data; Data Set; Deterioration; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Etiology; Exhibits; Family member; Fiber; Genes; Genetic; Genetic Risk; Geometry; Healthcare; Heritability; Image; Image Analysis; Imaging Techniques; Impairment; Individual; Infant; Language; Language Disorders; Link; Longitudinal Studies; Measurement; Memory impairment; Mental disorders; Methodology; Nature; Neurocognitive; Neurocognitive Deficit; Neurodevelopmental Disorder; North Carolina; Pathologic; Pathology; Patients; Play; Population; Population Genetics; Populations at Risk; Process; Psychotic Disorders; Reporting; Research; Research Personnel; Risk; Role; Schizophrenia; Severities; Short-Term Memory; Structural defect; Structure-Activity Relationship; Symptoms; Therapeutic Intervention; Time; TimeLine; Universities; Water; aged; biomarker identification; cognitive ability; cognitive change; cohort; emerging adult; executive function; high risk; high risk population; imaging genetics; in vivo; infancy; insight; medical schools; neurodevelopment; psychotic symptoms; therapeutic development; tractography; white matter; white matter change

Project Summary There is an overwhelming belief that schizophrenia (SZ) is a neurodevelopmental disorder, due to evidence that structural and cognitive changes emerge at different illness stages. The timeline of structural abnormalities and their relationship to cognitive pathologies, however, is poorly understood. Neurocognitive impairments, most prominently language and working memory deficits, are considered core features of SZ, but the developmental progression of these deficits varies. Language abilities appear to be reduced very early in those at genetic risk for SZ, and they remain stably reduced thereafter, whereas working memory abilities diverge from a healthy trajectory shortly before the onset of psychosis and further deteriorate with illness progression. The differential trajectories of language and working memory capabilities in SZ strongly suggest there are distinct underlying pathophysiological mechanisms. Evidence suggests that white matter plays a crucial role in brain development and maturation, and studies have linked microstructural abnormalities in white matter tracts to deficits in cognitive abilities in at-risk individuals and SZ patients. In order to elucidate the developmental timeline of the structure-function relationship between white matter and cognitive abilities in at risk individuals, we aim to characterize pathological alterations in white matter that correspond to neurocognitive deficits in SZ risk individuals. The proposed project will analyze already collected data from three genetic high risk cohorts that represent three key developmental stages of SZ risk: infancy, childhood, and early adulthood. This study will therefore provide insight into both early and late neurodevelopmental changes associated with SZ risk and enable the characterization of structural deficits within specific developmental windows. We plan to apply advanced diffusion tensor imaging methodologies along with tract geometry and free water imaging to the datasets, allowing for the identification and differentiation of localized white matter abnormalities that may be related to aberrant early neurodevelopmental or later maturational pathologies in vivo. This project has two primary hypotheses: 1) We hypothesize that deficits in language are related to stable structural differences originating in aberrant early neurodevelopmental processes, reflected by changes in fiber architecture (geometry) in white matter language tracts; 2) We hypothesize that the deterioration of working memory abilities is related to a transient or reactive pathology to the presence of a possible insult, and this is reflected by deviations from normal maturational trajectories in tracts underlying working memory.. This will be the first study to analyze white matter from genetically at-risk individuals across the range of neurodevelopment. This study will significantly impact our understanding of the timeline of biological mechanisms that underlie functional correlates associated with SZ risk while uncovering biomarkers linked to functional vulnerabilities and identifying windows when therapeutic interventions would be most effective.

项目摘要 有一个压倒性的信念，精神分裂症（SZ）是一种神经发育障碍，由于 有证据表明，结构和认知变化出现在不同的疾病阶段。结构性地震的时间轴 然而，对异常及其与认知病理学的关系知之甚少。神经认知 障碍，最突出的是语言和工作记忆缺陷，被认为是SZ的核心特征，但 这些缺陷的发展进程各不相同。语言能力似乎在很早的时候就降低了， 那些有SZ遗传风险的人，此后他们保持稳定减少，而工作记忆能力 在精神病发作前不久偏离健康轨道，并随着疾病进一步恶化 进展SZ的语言和工作记忆能力的差异轨迹强烈表明， 存在不同的潜在病理生理机制。 有证据表明，白色物质在大脑发育和成熟中起着至关重要的作用， 研究表明，白色物质束的微结构异常与高危人群的认知能力缺陷有关。 个体和SZ患者。为了阐明结构-功能的发展时间轴， 白色物质和认知能力之间的关系，我们的目标是表征 与SZ风险个体的神经认知缺陷相对应的白色物质的病理学改变。 拟议的项目将分析已经收集的三个遗传高风险队列的数据， 代表SZ风险的三个关键发展阶段：婴儿期、儿童期和成年早期。本研究将 因此，提供了与SZ风险相关的早期和晚期神经发育变化的见解， 能够在特定的发育窗口内表征结构缺陷。我们计划申请 先进的扩散张量成像方法沿着与管道几何和自由水成像， 数据集，允许识别和区分局部白色物质异常， 与体内异常早期神经发育或后期成熟病理有关。 该项目有两个主要假设：1）我们假设语言缺陷与以下因素有关： 稳定的结构差异起源于异常的早期神经发育过程，反映在变化 在白色物质语言束的纤维结构（几何学）中; 2）我们假设， 工作记忆能力与对可能的损伤存在的短暂或反应性病理有关， 这反映在工作记忆的底层区域偏离正常的成熟轨迹上。 这将是第一项研究，以分析白色物质从遗传风险的个人在整个范围内， 神经发育这项研究将极大地影响我们对生物学的时间轴的理解。 与SZ风险相关的功能相关机制，同时揭示与 功能脆弱性和确定治疗干预最有效的窗口。