Genetics, physical health, and brain perivascular spaces during early adolescence

The National Institute of Child Health and Human Development awarded $100,228 to the University of Southern California on September 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to support research characterizing brain perivascular space development and its genetic and environmental determinants during early adolescence.

The research leverages longitudinal neuroimaging, whole genome sequencing, wearable-derived physical health metrics, and biospecimen data from the NIH Adolescent Brain Cognitive Development (ABCD) study across two waves (baseline at ages 9–10 and year two at ages 11–12). The project will characterize normative perivascular space morphology from ages 9–12, examine associations between previously identified single nucleotide polymorphisms and perivascular space morphology, and assess relationships between physical health metrics and perivascular space development. Perivascular spaces are cerebrospinal fluid-filled structures surrounding cerebral blood vessels that form a key component of the brain's glymphatic system supporting nutrient transport, interstitial fluid exchange, and waste clearance during the metabolically demanding adolescent neurodevelopmental period.

USC's Department of Contracts and Grants serves as the recipient. Performance occurs in Los Angeles, California. The period of performance runs through May 26, 2029. This is a National Research Service Award supporting individual postdoctoral research training in a health-related area.

Abstract

Adolescence is a critical period of neurodevelopment characterized by dramatic structural reorganization and functional brain changes. These changes are highly metabolically demanding, making efficient transport of nutrients and clearance of waste particularly important during this period. Perivascular spaces (PVS), cerebrospinal fluid-filled spaces that surround cerebral blood vessels, are central to these processes. PVS are a key component of the brain's glymphatic system, working in concert with the blood- brain barrier to support solute delivery, interstitial fluid exchange, and waste clearance. While PVS morphology has been identified as a biomarker of neurodegenerative and cerebrovascular disease, the developmental origins of PVS variability remain poorly understood. Recent advances in MRI and segmentation techniques have enabled the study of PVS in healthy pediatric populations, however these studies are limited by a small n and cross-sectional design. Furthermore, no studies to date have explored the interplay between genetic and environmental factors in relation to PVS morphology during adolescence. Given the importance of the glymphatic system for maintaining brain homeostasis and supporting key neurobiological processes, a clearer understanding of PVS development during this sensitive window is critical for identifying early-life inherited and modifiable factors that shape brain health trajectories. The proposed nrsa research project will leverage two waves of data (baseline: 9-10 years, and year-two: 11-12 years) from the landmark NIH adolescent brain cognitive development (abcd) study-including longitudinal neuroimaging, whole genome sequencing, wearable-derived physical health metrics, and biospecimen data-to: 1) characterize normative PVS development from ages 9-12, 2) examine whether previously identified snps are associated with PVS morphology during adolescence, and 3) implement machine learning frameworks (i.e., xgboost, gene-by-environment-lasso) to identify physical health factors and gene-by-environment interactions that predict PVS morphology. The proposed training plan includes advanced coursework and mentorship in longitudinal modeling, genomics, neuroimaging, and machine learning. Alongside a growing foundation in neuroimaging and big data, these experiences will position the candidate to achieve their long-term career goal of becoming an independent developmental neuroscientist. By identifying modifiable physical health factors that buffer genetic risk for PVS dysfunction, this work will contribute critically to our understanding of the etiology of PVS dysfunction and, ultimately, transform child and adolescent brain health.