The Role of Dysmyelination in Cognitive Impairment of Psychotic Spectrum Disorders

髓鞘形成障碍在精神病谱系障碍认知障碍中的作用

• 批准号: 9018777
• 负责人: MARIANA LAZAR
• 金额: $ 49.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9018777
• 关键词: Address; Affect; Biological; Biological Assay; Biological Markers; Bipolar Disorder; Brain; Brain region; Brain-Derived Neurotrophic Factor; Characteristics; Choline; Chronic; Cognition; Cognitive; Cognitive deficits; Consensus; Control Groups; Critical Pathways; Data; Databases; Diffusion; Disease; Emotions; General Population; Genes; Genetic; Genetic Polymorphism; Goals; Health; High Prevalence; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Intelligence; Life; Liquid substance; Literature; Magnetic Resonance Spectroscopy; Measures; Mediating; Missense Mutation; Molecular; Mutation; Myelin; Nerve Growth Factor Receptors; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Oligodendroglia; Outcome; Pathway interactions; Patients; Perception; Population; Problem Solving; Property; Protons; Psyche structure; Psychopathology; Radial; Resistance; Risk; Role; Schizophrenia; Short-Term Memory; Siblings; Signaling Protein; Syndrome; Testing; Treatment Efficacy; Visual; Water; base; cognitive ability; cognitive function; cognitive process; cognitive skill; cohort; cost; density; disability; dysmyelination; endophenotype; exome; imaging biomarker; imaging genetics; improved; inter-individual variation; memory process; myelination; myoinositol; neuromechanism; neuropsychological; neurotrophic factor; operation; prevent; response; severe mental illness; sustained attention; white matter

 DESCRIPTION (provided by applicant): Psychotic spectrum disorders (PSD) are disabling severe mental syndromes with high prevalence. Among the PSD deficits, cognitive dysfunction represents a core characteristic shown to the best predictor of poor outcome and chronic disability. However, current therapies do not adequately address cognitive symptoms. This limitation reflects to a large degree the still incipient and incomplete understanding of the involved neural mechanisms. A significant predictor of cognitive ability in both healthy individuals and individuals on the psychotic spectrum is working memory capacity, a cognitive domain impaired in many forms of psychopathology. Our preliminary data, based on Diffusion Kurtosis Imaging (DKI) technique, suggest that a) in the healthy brain, interindividual variations in visual working memory capacity relates to a large degree to axonal density (measured by Axonal Water Fraction (faxon )) of the white matter pathways connecting brain regions known to be involved in working memory processes, b) white matter deficits in schizophrenia (SZ), a primary PSD syndrome, are driven by impairments in Extra-axonal Radial Diffusivity (RDextra), a putative marker of myelination, and c) visual working memory capacity associations to white matter microstructural properties are altered in SZ, a primary PSD disorder, with relationships with critical pathways connecting prefrontal and temporal brain regions no longer present or relating not to axonal density, but to RDextra, the putative marker of dysmyelination. Thus, supported by these preliminary data, the primary aims of this project are to test that: 1) visual working memory capacity and overall cognitive deficits in PSD are explained to a large degree by deficits in white matter microstructure and therefore 2) Diffusion Kurtosis Imaging (DKI) markers of dysmyelination are candidate neurobiological endophenotypes of PSD. The dysmyelination hypothesis will be validated using a corroborative approach that includes DKI, Magnetic Resonance Spectroscopy, and genetic assays. The results of this study may reveal more specific microstructural alterations of white matter and contribute to the understanding of the mechanisms underlying cognitive dysfunction in PSD. The proposed biomarkers may prove instrumental in characterizing treatment efficacy and identifying at risk individuals.

 描述（由适用提供）：精神病谱系障碍（PSD）正在使严重的精神综合症患病率高。在PSD定义中，认知功能障碍代表了最佳预测和慢性残疾的最佳预测指标所显示的核心特征。但是，当前的疗法不能充分解决认知症状。这种局限性在很大程度上反映了对所涉及的中性机制仍然不完整的理解。在健康个体和精神病谱系中，认知能力的重要预测指标是工作记忆能力，这是一种认知领域，在许多形式的心理病理学中受到了损害。我们的初步数据，基于扩散峰度成像（DKI）技术，表明a）在健康的大脑中，与轴突密度（通过轴突水位（FAXON（FAXON）测量）相关的视觉工作记忆能力的个体变化（通过轴突密度测量（FAXON（FAXON））与已知的ps ins schiia（schii）相关的白质大脑区域（schiz syndrome, are driven by impairments in Extra-axonal Radial Diffusivity (RDextra), a putative marker of myelination, and c) visual working memory capacity associations to white matter microstructural properties are altered in SZ, a primary PSD disorder, with relationships with critical pathways connecting prefrontal and temporary brain regions no longer present or relating not to axonal density, but to RDextra, the putative marker炎性障碍。 That, supported by these preliminary data, the primary aims of this project are to test that: 1) visual working memory capacity and overall cognitive deficiencies in PSD are explained to a large degree by definition in white matter microstructure and therefore 2) Diffusion Kurtosis Imaging (DKI) markers of dysmyelination are candidate neurobiological endophenotypes of PSD.将使用包括DKI，磁共振光谱和遗传测定的佐证方法来验证降解假设。这项研究的结果可能揭示了白质的更具体的微观结构改变，并有助于理解PSD中认知功能障碍的机制。拟议的生物标志物可能证明有助于表征治疗功效并确定处于风险的人。