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: 8838674
• 负责人: Joshua Lawrence Roffman
• 金额: $ 45.91万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838674
• 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; DNA Sequence Alteration; Data; Data Set; Development; Diet; Dietary intake; Disease; Dose; Early Intervention; Early intervention trials; Encapsulated; Epidemiologic Studies; Epidemiology; Executive Dysfunction; Exhibits; Exposure to; Folic Acid; Folic Acid Deficiency; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Variation; Genomics; Genotype; Government; Individual; Intake; Intervention; Link; MTHFR gene; Magnetic Resonance Imaging; Measures; Medical Genetics; Metabolic Pathway; Metabolism; Modeling; Mothers; Nutritional; Participant; Pathway interactions; Patients; Pattern; Perinatal Exposure; Pharmaceutical Preparations; Phenotype; Pregnancy; Protocols documentation; Psychotic Disorders; 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 intervention; 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、基因组学和神经影像学研究有关。精神分裂症患者表现出与阴性症状严重程度相关的低血叶酸水平，这种模式受到叶酸相关基因变异的强烈影响。我们小组最近进行的两项临床试验表明，补充叶酸对阴性症状有益，但仅适用于携带先前涉及的遗传变异的患者。我们还发现，在精神分裂症患者和健康人的额顶叶控制网络中，叶酸相关基因对功能和结构MRI测量的影响是一致的。这项工作表明：(1)叶酸相关基因在精神分裂症中发挥重要的临床作用，与治疗反应有关；(2)这些基因影响精神分裂症治疗难治性方面的脑系统。然而，叶酸代谢途径的遗传变异对大脑的影响仍然不完全清楚，饮食中叶酸摄入量与大脑结构和功能之间的关系也不完全清楚。此外，重要的是