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

脑脊液动力学在唐氏综合症和相关神经发育障碍婴儿大脑和行为发育中的作用

• 批准号: 10507609
• 负责人: Dea Garic
• 金额: $ 13.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507609
• 关键词: Abeta clearance; Address; Adult; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Axon; Behavioral; Behavioral Symptoms; Biological Markers; Blood Circulation; Brain; Brain imaging; Cerebrospinal Fluid; Characteristics; Child; Child Psychiatry; Childhood; Clinical; Clinical Research; Clinical assessments; Cognitive deficits; Complex; Data; Dementia; Development; Diffusion; Disease; Disease Progression; Down Syndrome; Early Intervention; Early Onset Alzheimer Disease; Foundations; Fragile X Syndrome; Functional disorder; Future; General Population; Goals; Health Sciences; Human; Image; Impairment; Infant; Intercellular Fluid; Intervention; K-Series Research Career Programs; Lead; Life; Link; Longitudinal Studies; Magnetic Resonance Imaging; Manuscripts; Measures; Meningeal lymphatic system; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Morphology; Motor; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurology; Neurosciences; Oregon; Outcome; Pathogenesis; Pathology; Pathway interactions; Pediatrics; Physics; Physiology; Proteins; Protocols documentation; Psychiatry; Radiology Specialty; Research; Research Project Grants; Risk; Role; Sampling; Scanning; Severities; Sleep Disorders; Specificity; Symptoms; Testing; Time; Training; Treatment Efficacy; Universities; Washington; Work; autism spectrum disorder; brain health; career; career development; cerebrospinal fluid flow; computer science; critical period; design; early detection biomarkers; glymphatic clearance; glymphatic dysfunction; glymphatic system; imaging modality; imaging study; improved outcome; infancy; lymphatic drainage; neurodevelopment; neuroimaging; neuroinflammation; pre-clinical; programs; rapid growth; relating to nervous system; solute; targeted treatment; white matter

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).

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计划，以利用 神经影像学的进步，从翻译动物模型中发现和强大的临床评估 在婴儿期关键时期内识别大脑发育中的早期病理，干预可以使 最大的影响。最终，我的目标是改善神经发育障碍儿童（NDDS）的结果， 通过为唐氏综合症（DS）的重点，通过贡献将扩大我们对早期大脑的理解的工作 开发并为个性化的，有针对性的干预措施和非侵入性标记以提高治疗效率。 研究项目：Glycatic系统和脑膜淋巴引流的最新发现 强调脑脊液（CSF）对于通过清除来维持大脑健康至关重要 神经炎症蛋白（例如淀粉样蛋白β，Aβ），而CSF流量受损会减慢Aβ和 阿尔茨海默氏病的发病机理已隐含。大约50％的DS儿童将 发展早期发作的阿尔茨海默氏症，比普通人群早数十年。但是，我们的 对CSF动力学的了解仅限于对成年人衰老的研究，而对婴儿的临床研究 缺乏NDD（例如DS）。在婴儿期，大脑经历快速生长，尤其是 容易受到CSF异常的影响，但是在这种敏感的情况下，了解CSF生理存在危险的差距 时期及其与NDD的早期大脑发展的关系。鉴于患有DS的孩子在 阿尔茨海默氏症的风险大大更大，迫切需要研究DS婴儿的CSF动态 识别早期的，无创的生物标志物的疾病严重程度和进展，并指导个性化，针对性 治疗。我们旨在利用婴儿中的非侵入性MRI方法来评估三种CSF生理学措施 （轴外CSF体积，血管周围空间大小和CSF流动）；它们与临床表现的关系 DS;并与相关的NDD（自闭症和脆弱X综合征）进行了比较。具体目的：（1）阐明轨迹 患有DS的婴儿的CSF动力学并与其他NDD对比以确定特异性； （2）确定 CSF动力学与（2a）神经和（2B）DS和相关NDD的临床特征之间的关系。 职业发展：该K01奖将为我提供CSF中必要的跨学科培训 成像，CSF病理生理学以及DS和NDD的早期神经和行为特征，以启动我 独立职业。指导团队包括NDDS中CSF异常的临床和临床前专家， 胶囊系统以及婴儿的CSF和大脑成像：共同发源地：Drs。马克·沉（精神病学系和 神经科学，UNC）和Jeffrey Lliff（华盛顿大学神经病学系）。顾问：博士。约瑟夫·皮文（Joseph Piven） （精神病学，UNC），罗伯特·麦金斯特里（Robert McKinstry）（华盛顿大学放射学），胡安·皮安蒂诺（Juan Piantino）（儿科，俄勒冈州 健康与科学大学）和Martin Styner博士（计算机科学，UNC）。