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).

PROJECT NARRATIVE Cerebrospinal fluid (CSF) pathophysiology has been associated with impaired clearance of neuroinflammatory proteins, (e.g., amyloid-beta) and implicated in neurodegenerative disorders such as Alzheimer’s disease, but the role of CSF dynamics in neurodevelopmental disorders remains unknown. This Career Development Award aims to address this gap by elucidating and contrasting trajectories of CSF characteristics in Down Syndrome (DS) and related disorders (autism spectrum disorder and Fragile X syndrome) across the first two years of life, to determine the relationships between CSF physiology and later neural and clinical features. Given that 50% of children with DS will go on to develop early-onset Alzheimer’s, CSF physiology can serve as a mechanistic pathway to aberrant brain and behavioral development and has the potential to guide the design of targeted treatment approaches for early intervention.