The Role of CSF Dynamics in Infant Brain and Behavioral Development in Down Syndrome and Related Neurodevelopmental Disorders

项目摘要 职业目标：我的长期职业目标是领导一个独立的研究项目，该项目将利用 神经成像的进展、来自翻译动物模型的发现和可靠的临床评估 在婴儿期的关键时期识别大脑发育的早期病理，此时干预可以使 影响最大。最终，我的目标是改善神经发育障碍(NDDS)儿童的预后， 以唐氏综合症(DS)为重点，通过贡献工作扩大我们对早期大脑的了解 开发和告知个人化、有针对性的干预措施和治疗效果的非侵入性标记。 研究项目：最近对淋巴系统和脑膜淋巴引流的发现 强调脑脊液(CSF)对维持大脑健康至关重要 神经炎性蛋白(例如，淀粉样β蛋白，Aβ)，而脑脊液流量受损会减缓Aβ和 与阿尔茨海默病的发病机制有关。大约50%的患有DS的儿童将 罹患早发性阿尔茨海默氏症，比一般人群早几十年发病。然而，我们的 对脑脊液动力学的了解仅限于对老年人的研究，而对婴儿的临床研究 缺乏NDD(如DS)。在婴儿期，大脑经历快速增长，特别是 很容易受到脑脊液异常的影响，但在这一敏感时期，对脑脊液生理学的理解存在严重差距 以及它与NDDS早期脑发育的关系。鉴于患有DS的儿童处于一种 阿尔茨海默氏症的风险大大增加，迫切需要研究DS-TO婴儿的脑脊液动力学 识别疾病严重程度和进展的早期、非侵入性生物标志物，并指导个性化、有针对性的 治疗。我们的目标是在婴儿中使用无创性mri方法来评估脑脊液生理的三个指标。 (轴外脑脊液体积、血管周围间隙大小和脑脊液流量)；它们与脑脊液综合征临床表现的关系。 DS；并与相关的NDDS(自闭症和脆性X综合征)进行比较。具体目标：(1)阐明轨迹 检测DS患儿的脑脊液动力学，并与其他NDDS进行对比，以确定特异性；以及(2)确定 DS及相关NDDS的脑脊液动力学与(2a)神经和(2b)临床特征的关系 职业发展：这一K01奖项将为我提供必要的跨学科培训 DS和NDDS的影像、脑脊液病理生理学和早期神经和行为特征 独立的事业。导师团队包括NDDS中脑脊液异常的临床和临床前专家， 婴儿的淋巴系统、脑脊液和脑成像：共同导师：马克·沈博士(科室)精神病学和 神经科学，北卡罗来纳大学)和Jeffrey Lliff(系华盛顿大学神经病学教授)。顾问：约瑟夫·皮文博士 (精神病学，北卡罗来纳州大学)，Robert McKinstry(放射学，华盛顿大学)，Juan Piantino(儿科，俄勒冈州) 健康与科学大学)和马丁·斯泰纳博士(计算机科学，北卡罗来纳大学)。

PROJECT ABSTRACT CAREER GOAL: My long-term career goal is to lead an independent program of research that will leverage advancements in neuroimaging, discoveries from translational animal models, and robust clinical assessments to identify early pathology in brain development during critical periods in infancy when intervention can make the greatest impact. Ultimately, I aim to improve outcomes in children with neurodevelopmental disorders (NDDs), with a focus on Down Syndrome (DS), by contributing to work that will expand our understanding of early brain development and inform personalized, targeted interventions and non-invasive markers for treatment efficacy. RESEARCH PROJECT: Recent discoveries of the glymphatic system and meningeal lymphatic drainage have highlighted that cerebrospinal fluid (CSF) is critically important for maintaining brain health by clearing neuroinflammatory proteins (e.g., amyloid-beta, Aβ), whereas impaired CSF flow slows the clearance of Aβ and has been implicated in the pathogenesis of Alzheimer’s disease. Approximately 50% of children with DS will develop early-onset Alzheimer’s, occurring decades earlier than the general population. However, our understanding of CSF dynamics has been limited to studies in aging adults, whereas clinical studies in infants with NDDs (such as DS) are lacking. During infancy, the brain undergoes rapid growth and may be particularly vulnerable to CSF abnormalities, but there is a critical gap in understanding CSF physiology during this sensitive period and how it relates to the early brain development of NDDs. Given that children with DS are at a substantially greater risk for Alzheimer’s, there is an urgent need to study CSF dynamics in infants with DS to identify early, non-invasive biomarkers of disorder severity and progression and to guide personalized, targeted treatments. We aim to utilize non-invasive MRI methods in infants to evaluate three measures of CSF physiology (extra-axial CSF volume, perivascular space size, and CSF flow); their relationships to clinical manifestations of DS; and compared to related NDDs (autism and Fragile X syndrome). Specific Aims: (1) Elucidate trajectories of CSF dynamics in infants with DS and contrast with other NDDs to determine specificity; and (2) determine the relationships between CSF dynamics and (2a) neural and (2b) clinical features of DS and related NDDs. CAREER DEVELOPMENT: This K01 award will provide me with the necessary cross-disciplinary training in CSF imaging, CSF pathophysiology, and early neural and behavioral features of DS and NDDs to launch my independent career. Mentorship team includes clinical and preclinical experts in CSF abnormalities in NDDs, glymphatic system, and CSF and brain imaging in infants: Co-mentors: Drs. Mark Shen (Dept. of Psychiatry and Neuroscience, UNC) and Jeffrey lliff (Dept. of Neurology, University of Washington). Advisors: Drs. Joseph Piven (Psychiatry, UNC), Robert McKinstry (Radiology, Washington University), Juan Piantino (Pediatrics, Oregon Health and Science University), and Dr. Martin Styner (Computer Science, UNC).