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

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).