MRI Studies of Folate-Related Genes, Diet, and Development: Promise for Psychosis

叶酸相关基因、饮食和发育的 MRI 研究：治疗精神病的希望

• 批准号: 8706977
• 负责人: Joshua Lawrence Roffman
• 金额: $ 67.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706977
• 关键词: Adolescent; Adult; Adverse effects; Affect; Age; Architecture; Area; Autistic Disorder; Biological Availability; Blood; Boston; Brain; Brain imaging; Case-Control Studies; Cereals; Child; Clinical; Clinical Trials; Collection; Conceptions; Coupled; DNA; Data; Data Set; Development; Diet; Dietary intake; Disease; Dose; Early Intervention; Early intervention trials; Encapsulated; Epidemiologic Studies; Epidemiology; Executive Dysfunction; Exhibits; Exposure to; Folate; Folic Acid; Folic Acid Deficiency; Functional Magnetic Resonance Imaging; Gene Mutation; Genes; Genetic; Genetic Variation; Genomics; Genotype; Government; Individual; Intake; Intervention; Link; MTHFR gene; Magnetic Resonance Imaging; Measures; Metabolic Pathway; Metabolism; Modeling; Mothers; Nutritional; Participant; Pathway interactions; Patients; Pattern; Perinatal Exposure; Pharmaceutical Preparations; Phenotype; Pregnancy; Protocols documentation; Psychotic Disorders; Public Health; Randomized Clinical Trials; Recruitment Activity; Refractory; Relative (related person); Resolution; Risk; Role; Schizophrenia; Severities; Structure; Supplementation; Symptoms; System; Thick; Variant; Vitamin B Complex; Work; absorption; base; clinical effect; cohort; design; fortification; genetic variant; high risk; improved; in utero; indexing; intervention effect; neurodevelopment; neuroimaging; neuropsychiatry; novel; prenatal; prospective; protective effect; public health relevance; treatment response

DESCRIPTION (provided by applicant): Folate deficiency has been implicated in epidemiologic, genomic, and neuroimaging studies of schizophrenia. Patients with schizophrenia exhibit low blood folate levels that correlate with negative symptom severity, a pattern that is strongly influenced by variation in folate-related genes. Two recent clinical trial by our group demonstrated a benefit of folate supplementation for negative symptoms, but only among patients who carried the previously implicated genetic variants. We have also seen consistent effects of folate-related genes on functional and structural MRI measures within the frontoparietal control network, in both patients with schizophrenia and healthy individuals. This work suggests that (1) folate-related genes exert important clinical effects in schizophrenia that are relevant to treatment response, and (2) these genes influence brain systems that underlie treatment-refractory aspects of schizophrenia. However, the effects of genetic variation across the folate metabolic pathway on the brain remain incompletely characterized, as does the relationship between dietary folate intake and brain structure and function. Also, importantly, the clinical benefit of folate supplementation in schizophrenia was relatively modest, even among individuals who carried predisposing genetic variants. Earlier exposure to folate augmentation, including during neurodevelopment, may confer a stronger benefit for at-risk individuals. Indeed, recent studies suggest that increased maternal folate intake early in pregnancy can reduce the risk of autism, especially among mothers who have low-functioning genetic variants in the folate metabolic pathway. The proposed study of healthy adults and adolescents will greatly extend our understanding of how folate influences the brain, as a prelude to developing improved folate-based interventions. We will focus on structural and functional measures in the frontoparietal control system that are consistently abnormal in schizophrenia, and that have been tied to folate-related genes. For Aim 1, we will leverage a large, existing collection of MRI data and DNA (>3,300 subjects) to conduct novel, polygene-score based analyses of genetic variation throughout the folate metabolic pathway. In Aim 2, we will recruit individuals across a range of polygene scores to determine how folate intake influences high-resolution structural and functional MRI indices. Using the same MRI measures, Aim 3 will leverage a recent large-scale public health intervention to examine effects of in utero folate exposure in two age-matched cohorts of healthy adolescents: one group will have gestated before mandatory folate fortification of grain products was implemented in 1998, and the other will have gestated after this intervention. This multi-tiered approach will allow us to comprehensively evaluate genomic (Aim 1), environmental (Aim 2), and neurodevelopmental (Aim 3) aspects of folate effects on the brain, both separately and in combination with each other. This work could have important implications for the use of targeted, high-dose folate augmentation as a preventative strategy, especially among young individuals at high risk for schizophrenia, or even pre-conception.

描述（由申请人提供）：叶酸缺乏与精神分裂症的流行病学，基因组和神经影像学研究有关。精神分裂症患者表现出低血叶酸水平，与阴性症状严重程度相关，这种模式受叶酸相关基因变异的强烈影响。我们小组最近的两项临床试验表明，叶酸补充了阴性症状，但仅在携带先前涉及的遗传变异的患者中。我们还看到了叶酸相关基因对精神分裂症和健康个体患者的额叶控制网络中功能和结构MRI测量的一致作用。这项工作表明（1）叶酸相关的基因在精神分裂症中发挥重要的临床作用，与治疗反应相关，（2）这些基因影响精神分裂症治疗难治性方面的脑系统。但是，整个叶酸代谢途径对大脑的遗传变异的影响仍然不完全表征，饮食叶酸摄入与大脑结构和功能之间的关系也是如此。而且，重要的是 叶酸补充在精神分裂症中的临床益处相对适度，即使在携带易感遗传变异的个体中。早期接触叶酸增强，包括神经发育期间，可能会为处于危险中的个体带来更大的好处。实际上，最近的研究表明，妊娠早期母体叶酸摄入量的增加可以降低自闭症的风险，尤其是在叶酸代谢途径中具有低功能遗传变异的母亲中。对健康成年人和青少年的拟议研究将极大地扩展我们对叶酸如何影响大脑的理解，这是发展基于叶酸的改善干预措施的前奏。我们将重点关注额心脏控制系统中始终异常异常的结构和功能测量，这些措施与叶酸相关的基因息息相关。对于AIM 1，我们将利用MRI数据和DNA（> 3,300名受试者）的大量集合来进行整个叶酸代谢途径的新型，基于聚光分数的遗传变异分析。在AIM 2中，我们将招募一个跨多边形评分的个体，以确定叶酸摄入如何影响高分辨率结构和功能性MRI指数。使用相同的MRI措施，AIM 3将利用最近的大规模公共卫生干预措施来检查在两种年龄匹配的健康青少年中的子宫叶酸暴露中的影响：一组将在1998年实施强制性叶酸强化谷物产品之前，并在此干预后进行妊娠。这种多层方法将使我们能够全面评估基因组（AIM 1），环境（AIM 2）和神经发育（AIM 3）叶酸对大脑的影响的方面，无论是分别且相互结合的。这项工作可能对使用有针对性的高剂量叶酸增加作为一种预防策略具有重要意义，尤其是在具有精神分裂症高风险的年轻人中，甚至是概念前。