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项目， 神经影像学的进步，转化动物模型的发现，以及可靠的临床评估 在婴儿期的关键时期确定大脑发育的早期病理学， 最大的影响。最终，我的目标是改善神经发育障碍（NDD）儿童的预后， 以唐氏综合症（DS）为重点，通过促进工作，将扩大我们对早期大脑的理解， 开发和告知个性化的、有针对性的干预措施和治疗效果的非侵入性标志物。 研究项目：最近发现的胶质淋巴系统和脑膜淋巴引流， 强调脑脊液（CSF）通过清除 神经炎性蛋白（例如，淀粉样蛋白β，Aβ），而受损的CSF流动减慢Aβ的清除， 与阿尔茨海默病的发病机制有关大约50%的DS儿童会 患上早发性老年痴呆症，比一般人群早几十年。但我们的 对CSF动力学的了解仅限于老年人的研究，而婴儿的临床研究 如：如：在婴儿期，大脑经历快速生长， 易受CSF异常的影响，但在这一敏感时期， 以及它与NDD早期大脑发育的关系。考虑到患有DS的儿童处于 阿尔茨海默氏症的风险大大增加，迫切需要研究DS婴儿的CSF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、靶向 治疗。我们的目的是利用非侵入性MRI方法在婴儿中评估CSF生理学的三个指标 （轴外CSF体积、血管周围间隙大小和CSF流量）;它们与 DS;并与相关的NDD（自闭症和脆性X综合征）进行比较。具体目标：（1）阐明轨迹 DS患儿CSF动力学的变化，并与其他NDD进行对比，以确定特异性;（2）确定 CSF动力学与DS和相关NDD的（2a）神经和（2b）临床特征之间的关系。 职业发展：这个K 01奖项将为我提供必要的CSF跨学科培训 影像学，CSF病理生理学，以及DS和NDD的早期神经和行为特征， 独立的职业生涯。导师团队包括NDD中CSF异常的临床和临床前专家， 胶质淋巴系统，以及婴儿CSF和脑成像：共同导师：Mark Shen博士（Dept.精神病学和 Neuroscience，Escherichia）和Jeffrey Lliff（Dept. of Neurology，University of华盛顿）。顾问：Joseph Piven博士 （精神病学，华盛顿），罗伯特·麦金斯特里（放射学，华盛顿大学），胡安·皮安蒂诺（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，麻省理工学院）。