# Cerebrospinal fluid abnormalities in neurodevelopmental disorders

> **NIH NIH P50** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $155,500

## Abstract

Cerebrospinal fluid (CSF) circulation is essential for removing neuroinflammatory proteins through a process that
involves the brain's newly discovered lymphatic system. Circulating CSF also delivers growth factors that help
regulate brain development. Aberrant CSF circulation can result in a pathogenic buildup of neuroinflammatory
proteins and alter brain growth. CSF serves to link the central nervous and immune systems, which are
dysfunctional in neurodevelopmental disorders (NDDs). In three independent cohorts, our team was the first to
report that children with idiopathic autism spectrum disorder (iASD) have increased CSF volume surrounding
the brain (extra-axial CSF; EA-CSF) from 6 months to 4 years of age (Shen et al., 2013; 2017; 2018). Excessive
EA-CSF was detectable at 6 months of age (prior to onset of the defining behavioral symptoms of ASD), was
correlated with severity of specific later symptoms, and predicted later diagnosis. We extended this research to
single-gene NDDs with varying degrees of overlapping and distinct symptoms with iASD and now present
preliminary data showing that these single-gene NDDs also have excessive EA-CSF volume. Our preliminary
data also indicate that rodent models of these NDDs have excessive EA-CSF, similar to the patient populations,
and reduced CSF circulation. Our new observations suggest that excessive EA-CSF may be a potential
biomarker of a shared pathophysiological process in multiple NDDs. This project will prospectively study infant
cohorts of multiple NDDs, and corresponding mouse models, to examine the overarching hypothesis that
excessive EA-CSF volume and impaired CSF circulation result in an accumulation of neuroinflammatory proteins
and are related to aberrant brain and behavior development. This proposal will: [1] leverage resources from
ongoing NIH-funded MRI studies of children with NDDs; [2] enlist a multidisciplinary team with expertise in CSF
abnormalities in children with NDDs, neurophysiology of NDD mouse models, mouse neuroimaging, infant
neuroimaging, clinical phenotyping of infants with NDDs, and the lymphatic system; and [3] utilize all three UNC
IDDRC research cores to address the following aims: Aim 1: To elucidate potential mechanisms underlying
excessive EA-CSF in selected NDD model mice. Aim 2: To examine relationships between EA-CSF volume,
CSF circulation, and brain and behavior features in children with etiologically-distinct NDDs. This research will
expand our knowledge of a new phenomenon – aberrant CSF physiology in the early development of NDDs –
by examining the mechanisms and brain and behavior correlates in NDDs and corresponding rodent models, to
provide important insights for: development of targeted treatments, potential predictive biomarkers of later
disease progression, and knowledge about CSF pharmacodynamics relevant to upcoming clinical trials in NDDs
using intrathecal CSF drug delivery.
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## Key facts

- **NIH application ID:** 10224310
- **Project number:** 5P50HD103573-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mark D Shen
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,500
- **Award type:** 5
- **Project period:** 2020-07-28 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224310

## Citation

> US National Institutes of Health, RePORTER application 10224310, Cerebrospinal fluid abnormalities in neurodevelopmental disorders (5P50HD103573-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224310. Licensed CC0.

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