Cerebrospinal fluid and the early brain development of autism

Abstract

Background: There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system.

Main body: This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment.

Conclusion: The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments.

Keywords: Autism spectrum disorder; Biomarkers; Brain development; Brain enlargement; Cerebrospinal fluid; Early risk signs; Extra-axial cerebrospinal fluid; Glymphatic system; Heterogeneity; Infancy; Lateral ventricles; Neural meningeal lymphatic system; Neuroinflammation; Stratification biomarker.

Fig. 1

Schematic of CSF circulation, CSF outflow systems, and the anatomy of various CSF compartments. CSF is produced by the choroid plexus in the ventricles, where it delivers growth factors to progenitor cells that originate on the surface of the ventricles, and then proliferate into neurons and migrate to form the cerebral cortex. CSF circulates from the lateral, third and fourth ventricles to the cisterns of the brain, and then flows into the subarachnoid space, where it envelops the cortical convexities of the brain (EA-CSF). Inset box: From the subarachnoid space, there is retrograde influx of CSF into the parenchyma, where CSF and interstitial fluid interact in the perivascular space, alongside blood vessels that course throughout the brain. Astrocytes lining the perivascular space aid in transporting fluid that removes inflammatory waste proteins (e.g., Aβ), which are continually secreted by neurons as byproducts of neuronal activity and would otherwise build up in the brain. Finally, fluid carrying these inflammatory waste products returns to the subarachnoid space (EA-CSF) and drains into meningeal lymphatic vessels and arachnoid granulations.

Fig. 2

a T2-weighted images of an infant with a normal MRI at 6 months of age, who was confirmed as having typical development at 2 years of age. b Similar T2-weighted images of an infant with excessive extra-axial CSF at 6 months, who was diagnosed with ASD at 2 years of age. [CSF is indicated as brighter regions in these images. Images are of a horizontal section (left), coronal section (middle), and sagittal section (right) through the brain.]

Fig. 3

Infants later diagnosed with autism spectrum disorder (ASD) had abnormally increased extra-axial CSF by 6 months, which remained significantly elevated through 24 months. [Least squares means are adjusted for age, sex, total cerebral volume, and scan site. Error bars ± 1 SEM. *p = .005 vs. both control groups (high risk-negative and vs. low risk-negative). Percent differences and Cohen’s d effect sizes are calculated in relation to the high risk-negative group.] (Adapted from Shen et al. [20])