Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study

Abstract

Background: We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism.

Methods: In this case-control MRI study, children with autism spectrum disorder or with typical development aged 2-4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset.

Findings: Between July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm³ [SE 3·33] in autism group vs 101·40 cm³ [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p<0·0001) uniquely contributed to enlarged head circumference in the autism spectrum disorder group (p=0·04). Increased extra-axial CSF volume was associated with greater sleep disturbances (p=0·03) and lower non-verbal ability (p=0·04). The machine learning algorithm correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83% (95% CI 76·2-88·3).

Interpretation: Increased extra-axial CSF volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder. Increased extra-axial CSF volume is detectable using conventional structural MRI scans from infancy through to age 3 years. These results suggest that increased extra-axial CSF volume could be an early stratification biomarker of a biologically based subtype of autism that might share a common underlying pathophysiology.

Funding: US National Institutes of Health.

Figure 1.. Brain images illustrating the appearance and quantification of extra-axial CSF.

(A) T1-weighted coronal images of a typically developing child with a normal MRI at 3 years of age. (B) T1-weighted coronal images of a child with ASD and increased extra-axial CSF at 3 years of age. (C-E) Quantification of extra-axial CSF. (C) Manual tracing of dura on successive coronal slices are summed to yield intracranial volume; (D) semi-automated tissue segmentation yields total cerebral volume; (E) resulting space between the dura and cortical surface yields extra-axial CSF volume. (See Supplementary Methods for more details.)

Figure 2.. The ASD group had significantly greater extra-axial CSF volume compared to TD group.

A plot of the raw values of EA-CSF volume for each individual and the modeladjusted least squares means (LSM) for each group are illustrated. The least squares mean of the ASD group was 15·1% greater than the TD group. (Least squares means and p-value are from the model with age, sex, body weight, and TCV as covariates. Error bars = ±1 SEM.)

Figure 3.. A plot of the model-predicted values of EA-CSF for each individual.

(These modelpredicted values were computed from the beta weights of all the variables in the full statistical model.)

Figure 4.. Relationship with head circumference at 3 years and at birth.

(A) Head circumference was significantly correlated with TCV in both groups. (B) Head circumference was also significantly correlated with extra-axial CSF volume in both groups. (C) Head circumference at birth was significantly correlated with later TCV at 3 years of age in both groups. (D) Head circumference at birth was significantly correlated with volume of extra-axial CSF at 3 years of age in the ASD group, but not TD group. (*Normalized head circumference at birth is corrected by gestational age.)

Figure 5.. Subgroups of high Extra-axial CSF have more sleep problems.

(A) A ratio of CSF-to-Brain volume was derived by dividing extra-axial CSF by total cerebral volume. The ASD group had greater extra-axial CSF even when accounting for brain size in this manner (covariates: age, sex, weight). ASD subgroups of CSF:Brain Volume were then determined using a cutoff of +1·5 SD above the TD mean. (B and C) The ASD group with higher levels of extra-axial CSF (>1·5 SD above TD mean) had more sleep problems indicated on two sleep assessments: the Children’s Sleep Habits Questionnaire (B) and the Child Behavior Checklist (C). (Error bars = ±1 SEM.)