Next Generation Diffusion MRI Biomarkers for Prodromal Schizophrenia

项目总结/摘要 精神分裂症是一种破坏性和衰弱性疾病，影响约1%的人口， 其特征在于一系列症状，包括妄想、幻觉、认知功能受损、情绪 干扰和社会退缩。关于精神分裂症的神经病理学知之甚少，但成像 对其最早期的研究有可能确定精神病发作前的最初病理痕迹。 新的研究方法现在允许临床医生调查前驱精神分裂症受试者（prosthesis） 他们的精神病症状减轻，并且有患精神分裂症的高风险。扩散 磁共振成像是一种有前途的成像技术，因为它一贯和可靠地识别异常 在精神分裂症的各个阶段然而，目前的扩散MRI生物标志物和分析方法具有局限性。 敏感性和特异性差的潜在的微观结构病理，这构成了进一步的障碍， 了解精神分裂症的病因，以及药物治疗的新进展。 该提案的目标是开发工具并应用下一代扩散MRI生物标志物，例如游离- 水成像、神经突密度、神经突取向分散和峰度。这些生物标志物改善了 这是目前可用措施的特异性和灵敏度，更适合于识别微妙的病理。 我们以前的研究表明，神经发育，神经炎症和神经变性 精神分裂症中涉及到微结构病理学。我们假设神经炎症是 显性病理负责触发减弱的精神病症状，而异常 神经发育改变了大脑的外观或生长方式，可能是精神病的易感因素。 使用下一代扩散MRI生物标志物可以区分这些微病变， 有助于解释它们与减弱的精神病症状的关联，并揭示它们在精神病发作中的作用。 大规模的研究，如北美前驱症状纵向研究（NAPLS），已经 收集了包括dMRI数据在内的大型MRI数据集，这些数据将提供给我们。我们的做法是 为了利用这些现有的数据并利用它来研究前驱症状的病理相关性， 不像以前的研究，重点是转换为SZ的风险。前所未有的大数据 （n>700）提供了足够的灵敏度来识别细微的前驱病变。 一个由计算机科学家和临床神经科学研究人员组成的训练有素的团队将致力于开发新的 下一代扩散MRI生物标志物的工具，以定位和表征神经生物学， 是前驱症状学的基础这项研究的结果将对我们的 了解精神分裂症初始阶段的生物学机制，并将导致 改善诊断和可能的新治疗方法，针对神经炎症等现象。

Project Summary/Abstract Schizophrenia is a devastating and debilitating disorder that affects about 1% of the population and is characterized by a range of symptoms including delusions, hallucinations, impaired cognitive function, mood disturbances and social withdrawal. Little is known about the neuropathology of schizophrenia, yet imaging studies of its earliest stages have the potential to identify initial pathologic traces preceding psychosis onset. New research approaches now allow clinicians to investigate prodromal schizophrenia subjects (prodromes) who experience attenuated psychotic symptoms, and are at high-risk for developing schizophrenia. Diffusion MRI is a promising imaging technique for prodromes, since it consistently and reliably identifies abnormalities in all stages of schizophrenia. However, current diffusion MRI biomarkers and analysis methods have limited sensitivity and poor specificity to the underlying microstructural pathology, which pose barriers to further understanding the etiology of schizophrenia, and to new developments in pharmacological treatment. The goal of this proposal is to develop tools and apply next generation diffusion MRI biomarkers, such as free- water imaging, neurite density, neurite orientation dispersion, and Kurtosis. These biomarkers improve specificity and sensitivity of currently available measures, and are more suited to identify subtle pathologies. Our previous research suggests that neurodevelopmental, neuroinflammatory and neurodegenerative microstructural pathologies are involved in schizophrenia. We hypothesize that neuroinflammation is the dominant pathology responsible for triggering attenuated psychotic symptoms, and that abnormal neurodevelopment, which changes how the brain appears or grows, may be a predisposition for psychosis. Using next generation diffusion MRI biomarkers can distinguish between these micropathologies, which will help explaining their association with attenuated psychotic symptoms, and reveal their role in psychosis onset. Large-scale studies, such as the North American Prodrome Longitudinal Study (NAPLS), have already collected large datasets of CHR that include dMRI data, and this data will be available to us. Our approach is to leverage from these existing data and utilize it to study the pathological correlates of prodromal symptoms, unlike previous studies that focused on risk for conversion to SZ. The assembled unprecedentedly large data (n>700) provide ample sensitivity to identify subtle prodromal pathologies. A highly trained team of computer scientists and clinical neuroscience researchers will work to develop novel tools for next generation diffusion MRI biomarkers in order to localize and to characterize the neurobiology that underlies prodromal symptomatology. The results of this study will have an important impact on our understanding of biological mechanisms underlying the initial stages of schizophrenia, and will lead to improved diagnosis and possibly new treatments that target such phenomena as neuroinflammation.